Beruflich Dokumente
Kultur Dokumente
BACHELOR OF PHARMACY
In the faculty of Pharmaceutical Sciences, Bharati Vidyapeeth Deemed University, Pune. By
Ashish Lavjibhai Gajera
Bharati Vidyapeeth Deemed University, POONA COLLEGE OF PHARMACY, Erandawane, Pune 411 038, INDIA. 2009-2010
CERTIFICATE
This is to certify that the work presented in the project entitled
Anti-diabetic Agents
For the degree of
Bachelor of Pharmacy
has been carried out by Ashish Lavjibhai Gajera in Bharati Vidyapeeth Deemed University, Poona College of Pharmacy, Pune, under, under the guidance of Prof. Dr. V. M. Kulkarni of Bharati Vidyapeeth Deemed University, Poona College of Pharmacy, Pune.
Date :
/04/2010
Place : Pune
Dr. K. R. Mahadik Principal, Poona College of Pharamcy, Bharati Vidyapeeth Deemed University, Erandwane, Pune-411 038
CERTIFICATE
This is to certify that the work presented in the project entitled
Anti-diabetic Agents
For the degree of
Bachelor of Pharmacy
has been carried out by Ashish Lavjibhai Gajera in Bharati Vidyapeeth Deemed University, Poona College of Pharmacy, Pune, under my guidance and to my satisfaction. This report is now ready for examination. Such materials, as obtained from other sources have been duly acknowledged in the project.
Date : /04/2010
Place : Pune
Prof. Dr. Vithal M. Kulkarni, Research Guide, Professor Emeritus, Poona College of Pharmacy, Erandwane, Pune-411 038 .
ACKNOWLEDGEMENT
I take this opportunity to express the deep sense of gratitude to my adored research guide Dr. V. M. Kulkarni, Emeritus Professor, Poona College of Pharmacy, Pune who continues to support my aspiration with lots of love and encouragement. I consider myself privileged to work under his generous guidance because I got the newer creative dimensions, thinking and analyzing capacity, positive attitude, which has always helped me in making things simple and pragmatic too. I will always remain indebted to him. My sincere thanks and remembrance to our Vice Chancellor Dr. S. S. Kadam, and our Principal Dr. K .R. Mahadik for their constant support, valuable suggestions and for making available the infrastructure with all the sophisticated instruments. I owe my special thanks to Dr. S. R. Dhaneshwar, Dr. S. H. Bhosale, Dr. (Mrs.) S. S. Dhaneshwar and Dr. (Mrs.) J. R. Rao for their kind support and dynamic co-operation. I also wish to thank all the faculty members of Poona College of Pharmacy for providing the mandatory and scholastic inputs during my course venture. Special thanks to my Ph. D senior Shah Ujashkumar for his constant support to complete this project. I would like to express my heartfelt gratitude to God, grandparents, my parents & my brother Ashwinbhai & Dayabhabhi and sister Anuradhdidi & Artididi, jiju Ghanshyamkumar & Parimalkumar and sweet Isha & Manthan for their love, affection, care, courage, and confidence to complete this project work. I cannot adequately express my deep sense of gratitude and heartfelt emotions for my family, who blessed me with their good wishes relieving all type of distress from me. I am thankful to all those who have directly or indirectly extended their help towards this project. Thankful I ever remain
INDEX
1. Introduction
1.1 Pre-diabetes 1.2 Diabetes 1.3 Etymology 1.4 Epidemiology 1.5 Insulin and diabetes mellitus 1.6 Pathophysiology of diabetes 1.7 Signs and Symptoms 1.8 History
1-15
1 1 6 6 7 8 9 11
2. Literature Review
2.1 History 2.2 Oral antidiabetic agent (Clinically used) 2.3 Oral antidiabetic agent (Clinically not used)
16-38
16 18 20
39-40
4. Insulin
4.1 Discription 4.2 Variants of Insulin products
41-46
42 42
5. Secretagogues
5.1 K+ ATP 5.1.1 Sulfonylureas
47-77
47 47
5.1.2 Meglitinide 5.2 GLP-I analogues 5.3 Protein Tyrosin Phosphate 1 inhibitors 5.4 Dipeptidyl peptidase-4 inhibitors
60 63 65 72
6. Sensitizers
6.1 Biguanide 6.2 Thiazolidinedione 6.3 PPAR modulator
78-89
78 82 87
90-95
90 91 91 91 92
8. Other analogues
8.1 -Glucosidase inhibitor 8.2Amylin 8.3 Sodium-glucose transport proteins
96-103
96 100 102
LISTS OF FIGURE
Title Normal insulin signaling pathways Complications of diabetes mellitus Primary structure of proinsulin, depicting cleavage sites to produce insulin.
Page No 8 10 41
Insulin structure Classification of PTP Role of PTP-1 in insulin signaling Structure of PTP-1 showing main sites Structure of PTP-1 showing simultaneous dephosphorylation of insulin receptor
42 66 67 68 69
Dipeptidyl peptidase-4 inhibitor PPAR and pathways. Amino acid sequence of Amylin with disulfide bridge and cleavage sites of insulin degrading enzyme indicated with arrows
72 87 100
ANTI-DIABETIC AGENTS
DIABETES
1. INTRODUCTION1-20
1.1 Pre-diabetes
Prediabetes is a stage between normal and diabetes stage. It is an alarming sign for upcoming diabetes or a chance to change your future. Universally, numerous terms are given like, Borderline Diabetes, Chemical Diabetes, Touch of Diabetes etc. The term Prediabetic was given by the US Department of Health And Human Services on 27th march 2002 with an intention to create awareness and convey seriousness of the condition. Also, they motivated people to option for appropriate treatment and lifestyle modification. According to that 17 million US citizens are diabetic and 16 millions are prediabetic. It defines it as a stage before the development of diabetes, with normal glucose tolerance, but with an increased risk of developing diabetes in near future. Prediabetes is a condition when your blood sugar level triggers higher than normal, but not so high that we can justify it as type 2 diabetes. According to the Centers for Disease Control and Prevention, 41 million U.S. adults aged 40 to 74 have prediabetes. And the same reports from, The American Academy of Pediatrics show that, one of every 10 males and one of every 25 females have prediabetes aged from 12 to 19 years.
1.2 Diabetes
Diabetes is a disease in which levels of blood glucose, also called blood sugar, are above normal. People with diabetes have problems converting food to energy. Normally, after a meal, the body breaks food down into glucose, which the blood carries to cells throughout the body. Cells use insulin, a hormone made in the pancreas, to help them convert blood glucose into energy. People develop diabetes because the pancreas does not make enough insulin or because the cells in the muscles, liver and fat do not use insulin properly, or both. As a result, the amount of glucose in the blood increases while the cells are starved of energy. Over the years, high blood glucose, also called hyperglycemia, damages nerves and blood
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vessels, which can lead to complications such as heart disease, stroke, kidney disease, blindness, nerve problems, gum infections, and amputation. As per global projections by International Diabetes Federation (IDF), the number of diabetes patients has risen sharply in recent years. While in 1985, 30 million people had diabetes worldwide; the number rose to 150 million in 2000, 285 million in 2010 and is estimated to be 435 million - 7.8% of the adult world population by 2030.India has the highest number of diabetics in the world. By next year, the country will be home to 50.8 million diabetics, making it the world's unchallenged diabetes capital. And the number is expected to go up to 87 million -8.4% of the country's adult population -- by 2030. Diabetes mellitus is a common disease in the all over world.The crude prevalence rate of diabetes in urban areas is about 9% and that the prevalence in rural areas has also increased to around 3% of the total population. If one takes into consideration that the total population of India is more than 1000 million then one can understand the sheer numbers involved. Taking an urban-rural population distribution of 70:30 and an overall crude prevalence rate of around 4%, at a conservative estimate, India is home to around 40 million diabetics and this number is thought to give India the dubious distinction of being home to the largest number of diabetics in any one country. Diabetes prevalence has increased steadily in the last half of this century and will continue rising among U.S. population. It is believed to be one of the main criterions for deaths in United States, every year. This diabetes information hub projects on the necessary steps and precautions to control and eradicate diabetes, completely. Diabetes is a metabolic disorder where in human body does not produce or properly uses insulin, a hormone that is required to convert sugar, starches, and other food into energy. Diabetes mellitus is characterized by constant high levels of blood glucose (sugar). Human body has to maintain the blood glucose level at a very narrow range, which is done with insulin and glucagon. The function of glucagon is causing the liver to release glucose from its cells into the blood, for the production of energy. There are three main types of diabetes:
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can be observed in a diabetic. Desired blood sugar of human body should be between 70 mg/dl -110 mg/dl at fasting state. If blood sugar is less than 70 mg/dl, it is termed as hypoglycemia and if more than 110 mg /dl, its hyperglycemia. Diabetes is the primary reason for adult blindness, end-stage renal disease (ESRD), gangrene and amputations. Overweight, lack of exercise, family history and stress increase the likelihood of diabetes. When blood sugar level is constantly high it leads to kidney failure, cardiovascular problems and neuropathy. Patients with diabetes are 4 times more likely to have coronary heart disease and stroke. Gestational diabetes is more dangerous for pregnant women and their fetus. Though, Diabetes mellitus is not completely curable but, it is controllable to a great extent. So, you need to have thorough diabetes information to manage this it successfully. The control of diabetes mostly depends on the patient and it is his/her responsibility to take care of their diet, exercise and medication. Advances in diabetes research have led to better ways of controlling diabetes and treating its complications.
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3. Diseases of exocrine pancreas Pancriatitis Trauma/pancreatectomy Neoplasia Cystic fibrosis Hemochromatosis Fibrocalculous pancreatopathy 4. Endocrinopathies Acromegaly Cushings syndrome Glucagonoma Pheochromocytoma Hyperthyroidism Somatostatinoma Aldosteronoma 5. Drug or chemical induced Vacor Pentamidine Nicotinic acid Glucocorticoids Thyroid hormone Diazooxide -Adrenergic agonists Thiazides Dilantin Interferon 6. Infections Congenital rubella Cytomegalovirus
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7. Uncommon forms of immune mediated diabetes Stiff-man syndrome Klinefelters syndrome Turners syndrome Wolframs syndrome Friedeichs ataxia Huntingtons chorea Laurence-Moon-Biedel syndrome Porphyria Prader-Willi syndrome
1.3 Etymology
The word diabetes was coined by Aretaeus (81133 CE) of Cappadocia. The word is taken from Greek diabanein, and literally means passing through, or siphon. "Mellitus" comes from the Greek word "sweet". Apparently, the Greeks named it thus because the excessive amounts of urine diabetics produce (when blood glucose is too high) attracted flies and bees because of the glucose content. The ancient Chinese tested for diabetes by observing whether ants were attracted to a person's urine; medieval European doctors tested for it by tasting the urine themselves, a scene occasionally depicted in Gothic reliefs.The word became diabetes from the English adoption of the medieval Latin, diabetes. In 1675, Thomas Willis added mellitus to the name (Greek mel honey, sense honey sweet) when he noted that a diabetics urine and blood has a sweet taste (first noticed by ancient Indians). It is probably important to note that passing abnormal amounts of urine is a symptom shared by several diseases (most commonly of the kidneys), and the single word diabetes is applied to many of them. The most common of them are diabetes insipidus and the subject of this article, diabetes mellitus.
1.4 Epidemiology
Diabetes mellitus is a disease that occurs worldwide and the incidence is higher in relatives of diabetes, people older than 45 years and those who are currently or were obese. Studies of identical twins show greater than 94% concordance for developing NIDDM.
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Furthermore, there is a high prevalence of NIDDM in offsprings of parents with the disease and also in siblings of affected individuals. Persons more than 20 % over ideal body weight also have a greater risk of developing NIDDM. In addition, previously identified impaired glucose tolerance, gestational diabetes, hypertension or significant hyperlipidemias are associated with an increased risk of NIDDM.
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After insulin is bound the receptors aggregate and are rapidly internalized. Tyrosine kinase gets autophosphorylated and also phosphorylates other substrates so that a signaling cascade is initiated and biological response ensues.
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Type 2 DM results from a combination of relative deficiency in insulin production from the beta cell and insulin resistance at the target cell (liver, muscle and fat). Owing to heterogeneous nature of NIDDM and two major pathogenic factors influence one another, it is difficult to determine which of the two is initializing factor and what is relative contributions to the development of glucose intolerance.
Complication:
A well control diabetic is less labile to ketosis and infections. It is now certain that good control of glycemia mitigates the serious microvascular complications, retinopathy, nephropathy and cataract. Too light control of glycemia can increase the frequency of attacks of hypoglycemia. Diabetic ketoacidosis is caused by insulin deficiency and an increase in catabolic hormones, leading to hepatic overproduction of glucose and ketone bodies. Hyperglycemia causes a profound osmotic diuresis leading to dehydration and electrolyte loss, particularly of sodium and potassium. The metabolic acidosis forces hydrogen ions into cells, displacing potassium ions, which may be lost in urine or through vomiting. The signs and symptoms include polyuria, weight loss, thirst, abdominal pain, nausea, and vomiting. Hypotension, hypothermia and air hunger may also be present. Nonketotic hyperosmolar coma is characterized by severe hyperglycemia (>50 mmol/l) without significant hyperketonemia or acidosis. This condition usually affects elderly patients, many with previously undiagnosed diabetes. Mortality is over 40%.
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Diabetic retinopathy is the most common cause of blindness in adults between 30 and 65 years of age in developed countries. Clinical features of diabetic retinopathy include microaneurysms, retinal haemmorhages, hard exudates, soft exudates and fibrosis. Cataracts also are associated with the disease. Diabetic neuropathy occurs mainly due to axonal degeneration of both myelinated and unmyelinated fibres (Axonal shrinkage, Axonal fragmentation; regeneration),
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thickening of schwan cell basal lamina, patchy segmental demyelination and abnormalities in intraneural capillaries. This is relatively early and common complication affecting approximately 30% of diabetic patients. Diabetic foot occurs as a result of trauma in the presence of neuropathy and / or peripheral vascular disease, with infection occurring as a secondary phenomenon following ulceration of protective epidermis. In most cases all the three components are involved but sometimes neuropathy or ischaemia may predominate. In Diabetic nephropathy pathologically the first changes (at the time of microalbuminurea) are thickening of glomerular basement membrane and accumulation of matrix material in the mesangium. Subsequently, nodular deposits are characteristic, and glomerulosclerosis worsens (time of heavy proteinurea) glomeruli are progressively lost and renal function deteriorates.
1.8 History
Diabetes mellitus is known to the human beings many years ago mainly from prehistoric times. In earlier day, a clinical diagnosis of diabetes was an invariable death sentence, more or less quickly. Even non-progressing type 2 diabetes was left undiagnosed. But with the discovery of insulin, its treatment is made possible. Diabetes was first identified by Egyptians about 3500 years ago. It has been explained in the medical books of the ancient civilizations of Egypt, Greece, Indian, Rome and China. In the ancient books it has been mentioned that the disease is associated with polyuria, polydipsia, polyphagia, etc. A Roman citizen has described diabetes as a melting down of the flesh and limbs into urine. Moreover, the Charaka and Sushruta well known Ayurvedic physician, described that the diabetic patients passes sweet urine in large amount that is rain of honey. So, They have named Diabetes mellitus as Madhumeha. Thereafter, we can say diabetes has been recognized since antiquity, and its treatments were known since the middle ages. But the etiopathogensis of diabetes occurred mainly in the 20thcentury. The ancient Chinese have tested for diabetes by observing whether ants were attracted to a persons urine or not. Medieval European doctors have tested for diabetes, by testing the urine of diabetic patients themselves, a scene occasionally depicted in Gothic relief, and they named it sweet urine disease.
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1552 B.C.
Earliest known record of diabetes mentioned on 3rd Dynasty Egyptian papyrus by physician Hesy-Ra; mentions polyuria (frequent urination) as a symptom.
Diabetes described by Arateus as 'the melting down of flesh and limbs into urine.' Greek physician Galen of Pergamum mistakenly diagnoses diabetes as an ailment of the kidneys. Diabetes commonly diagnosed by 'water tasters,' who drank the urine of those suspected of having diabetes; the urine of people with diabetes was thought to be sweet-tasting. The Latin word for honey (referring to its sweetness), 'mellitus', is added to the term diabetes as a result.
Century
Paracelsus identifies diabetes as a serious general disorder. First chemical tests developed to indicate and measure the presence of sugar in the urine. French physician, Priorry, advises diabetes patients to eat extra large quantities of sugar as a treatment. French physician, Bouchardat, notices the disappearance of glycosuria in his diabetes patients during the rationing of food in Paris while under siege by Germany during the Franco-Prussian War; formulates idea of individualized diets for his diabetes patients.
19 Century
th
workings of the pancreas and the glycogen metabolism Czech researcher, I.V. Pavlov, discovers the links between the nervous system and gastric secretion, making an important contribution to science's knowledge of the physiology of the digestive system.
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Italian diabetes specialist, Catoni, isolates his patients under lock and key in order to get them to follow their diets.
1869
Paul Langerhans, a German medical student, announces in a dissertation that the pancreas contains contains two systems of cells. One set secretes the normal pancreatic juice, the function of the other was unknown. Several years later, these cells are identified as the 'islets of Langerhans.'
1889
Oskar Minkowski and Joseph von Mering at the University of Strasbourg, France, first remove the pancreas from a dog to determine the effect of an absent pancreas on digestion.
1900-1915
'Fad' diabetes diets include: the 'oat-cure' (in which the majority of diet was made up of oatmeal), the milk diet, the rice cure, 'potato therapy' and even the use of opium!
1908
German scientist, Georg Zuelzer develops the first injectible pancreatic extract to suppress glycosuria; however, there are extreme side effects to the treatment.
1910-1920
Frederick Madison Allen and Elliot P. Joslin emerge as the two leading diabetes specialists in the United States. Joslin believes diabetes to be 'the best of the chronic diseases' because it was 'clean, seldom unsightly, not contagious, often painless and susceptible to treatment.'
1913
Allen, after three years of diabetes study, publishes Studies Concerning Glycosuria and Diabetes, a book which is significant for the revolution in diabetes therapy that developed from it.
1919
ANTI-DIABETIC AGENTS
the Treatment of Diabetes, citing exhaustive case records of 76 of the 100 diabetes patients he observed, becomes the director of diabetes research at the Rockefeller Institute. 1919-20 Allen establishes the first treatment clinic in the USA, the Physiatric Institute in New Jersey, to treat patients with diabetes, high blood pressure and Bright's disease; wealthy and desperate patients flock to it. October 31, 1920 Dr. Banting conceives of the idea of insulin after reading Moses Barron's 'The Relation of the Islets of Langerhans to Diabetes with Special Reference to Cases of Pancreatic Lithiasis' in the November issue of Surgery, Gynecology and Obstetrics. For the next year, with the assistance of Best, Collip and Macleod, Dr. Banting continues his research using a variety of different extracts on de-pancreatized dogs. Summer 1921 December 1921 30, Insulin is 'discovered'. A de-pancreatized dog is successfully treated with insulin. Dr. Banting presents a paper entitled 'The Beneficial Influences of Certain Pancreatic Extracts on Pancreatic Diabetes', summarizing his work to this point at a session of the American Physiological Society at Yale University. Among the attendees are Allen and Joslin. Little praise or congratulation is received. 1940s 1944 1955 1959 Link is made between diabetes and long-term complications (kidney and eye disease). Standard insulin syringe is developed, helping to make diabetes management more uniform. Oral drugs are introduced to help lower blood glucose levels. Two major types of diabetes are recognized: type 1 (insulin-dependent) diabetes and type 2 (non insulinPage 14
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dependent) diabetes. 1960s The purity of insulin is improved. Home testing for sugar levels in urine increases level of control for people with diabetes. 1970 Blood glucose meters and insulin pumps are developed. Laser therapy is used to help slow or prevent blindness in some people with diabetes. 1983 1986 1993 First biosynthetic human insulin is introduced. Insulin pen delivery system is introduced. Diabetes Control and Complications Trial (DCCT) report is published. The DCCT results clearly demonstrate that intensive therapy (more frequent doses and self-adjustment according to individual activity and eating patterns) delays the onset and progression of long-term complications in individuals with type 1 diabetes. 1998 The United Kingdom Prospective Diabetes Study (UKPDS) is published. UKPDS results clearly identify the importance of good glucose control and good blood pressure control in the delay and/or prevention of complications in type 2 diabetes.
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2. LITERATURE SURVEY21-39
2.1 History
The discovery of insulin in 1922 by Benting, Best, Mac Leod and Collip, confirmed on the one hand the role of pancreas as an endocrine gland and the part it plays in the pathogenesis of diabetes, a fact which had also been indicated initially by the research of Minkowisky and of Hedon. Insulin was isolated in the crystalline form by Abel in 1926. On the other hand it provided many diabetic patients with an effective form of treatment allowing them to lead almost normal lives. It is immediately apparent that insulin did not cure diabetes, that its beneficial effects did not last more than a few hours, that injections needed to be repeated throughout the day and that such treatment would have to be carried out immediately. It was also shown that insulin was rapidly inactivated when it was administered via the digestive tract. Attempts to treat human diabetes by orally administered pharmacological agents like synthalins and their derivatives, were made between 1925 to 1930, these substances were quickly abandoned by their advocates however because of their variability, the appearance of toxic side effects and of the uncertainty concerning their mode of action. After the earlier therapeutic failures of the synthalins, attempts were made to prolong the 6-8 hour effects of the single injection of soluble insulin to obviate the necessity for repeated injections. This was done by coupling the hormone to zinc and then to certain protamines, which are other agents, prolonging the effects of ordinary insulin, producing protamine-zinc-insulin (PZI), which after a single injection could maintain effects for 24 hrs in certain cases, longer. Between 1939 and 1942, the therapeutic use of the sulfonamide increased dramatically and the drugs were assessed end tried in the treatment of many infectious diseases.
H 2N
SO2NH
S N N
CH3 CH3
VK-57 (2254RP) P-amino-benzene-sulfonamide-isopropyl-thiadiazole (VK-57) was synthes -ized in 1941 by Von Kennel and Kimming. This drug had shown a certain in vitro inhibitory
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effect on multiplication of the typhoid bacillus. After oral doses of 2254RP some patients died from obscure causes, which were only elucidated later when the hypoglycemic action of the sulfonamide became clear, it was strongly suggested that they died from severe and prolonged hypoglycemia. Several experiments were done in different animal models to explain the hypoglycemic effect of sulfonamide. It was postulated that sulfonamide act by stimulating the beta cells of the islets and liberate in to the blood an accumulated quantity of endogenous insulin (insulin secretory action).
H2N
SO2NHCONHCH2CH2CH2CH3
Carbutamide (BZ55) German workers published that a new sulfonamide i.e.1-butyl-3-sulfonylurea (carbutamide or BZ55) was more active than 2254 RP as hypoglycemic agent. 2254 RP and carbutamide have a NH2 group in the para position on the benzene ring and because of this have a bacteriostatic action, which could be considered unnecessary if not a major disadvantage. In 1956, a group of german workers published the experimental and clinical results obtained by using a sulfonamide with its NH2 group in the para position replaced by CH3 group but with the reminder of the molecule possessing a structure identical to that of carbutamide. This substance D860, 1-butyl-3-tolyl-sulfonylurea (tolbutamide) which did not have bacteriostatic action and retained the hypoglycemic and antidiabetic properties of 2254RP and carbutamide.
H3C
SO2NHCONHCH2CH2CH2CH3
Tolbutamide
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Cl
SO2NHCONHCH2CH2CH3
Chlorpropamide
H3C
SO2NHCONH
Tolazamide
OMe
SO2NHCONH
Acetohexamide
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H3 C
SO2NHCONH
Gliclizide
Second-generation sulfonylureas: Second generation sulfonylureas are very potent compounds and their dose is low. Some examples are as follows:
OMe CONHCH2CH2 Cl SO2NHCONH
Glibenclamide
N H3C N CONHCH2CH2 SO2NHCONH
Glipizide 2) Biguanides:
The only nonsulfonylurea drugs, which have proven useful in antidiabetic therapy, are the biguanides17, which can be used either alone or in combination with sulfonylureas. Only three agents are marketed at the present time (Metformin, Chenformin and Buformin).
H3C H3C NH N C NH NH C NH2
Metformin
NH NH C NH2
NH H2CH2C NH C
Phenformin (Chenformin)
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NH H3CH2CH2CH2C NH C NH
NH C NH2
Buformin Two factors have recently emerged which adversely affect the use of biguanides. Phenformin was one of the drugs examined in the university group Diabetes program (UGDP) study and as in the case of tolbutamide, enhanced cardiovascular mortality was observed instead of the anticipated beneficial effects. These findings were judged to be severe enough to warrant an early termination of phenformin study. Again, the conclusion of the UGDP study group have aroused controversy, and its conclusions have been questioned. It is certainly interesting that a group from England found a reduced incidence of myocardial infarction in a 5-year study of phenformin and that another group found a slight but insignificant beneficial effects of phenformin on survival in patients with coronary heart disease. It is therefore not clear at this time whether the use of phenformin is associated with increased cardiovascular mortality only in diabetes or whether the findings with phenformin can be generalized to other biguanides.
An interesting newer structure is meglitinide (HB-669), which is related to Glibenclamide, with a carboxyl group replacing the acidic sulfonylurea function. HB-669 and its higher homologue (HB-093) are insulin releasers although their potency is much more than that of Glibenclamide and more in the range of tolbutamide. It should be interesting to see whether or not will prove efficacious in man. Similarly, a benzoic acid derivative has hypoglycemic properties, and the S-enantiomer is more potent than Renantiomer. This suggest that the high potency side chain of both sulfonylureas and benzoic acids interact at the same receptor.
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OMe CONHCH2CH2 Cl
Meglitinide
OMe CONHCH2CH2 Cl CH2CH2COOH
COOH
Salicylates have been used long ago to improve glucose control in diabetes, possibly via their insulin-releasing or antilipolytic effects. However, high doses are required and the clinical benefits appear to be marginal.
OH COOH
H3C
OH COOH
The benzoic acid derivatives have been reported to stimulate glucose utilization, but it apparently had side effects and caused tachyphylaxis in animals.
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COOH Cl N
3-Mercaptopicolinic acid and several derivatives are apparently gluconeogenesis inhibitors, which lower glucose levels in animals.
SH N
3) Heterocyclic Carboxylic Acid: A series of heterocyclic carboxylic acids and their metabolic precursors generated some excitement a few years ago because these antilipolytic compounds lowered blood glucose in diabetics. 4) Heterocyclic Acids:
COOH
H3C N O COOH
H3C N N H CH3
H3C N O CH3
6) Aliphatic Carboxylic Acids: Among aliphatic carboxylic acids, dichloroacetic acid in the form of its diisopropylammonium or sodium salt, has been shown to lower blood glucose and to remedy the lactate elevations found after phenformin treatment.
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7) Dichloroacetic Acid:
Cl2CHCOOH
8) Diisopropyl Derivative:
HOOCCOCH2COOH
9) Oxirane Carboxylic Acid: Oxirane carboxylic acid and its methyl esters are reported to be inhibitors of carnitine acyl transferase and to be hypoglycemic in fasted, diabetic, or fat fed animals, by enhancing peripheral glucose oxidation.
H29C14
COOH O
NH2 COOH
H29C14
COOCH3 O
COOH
10) Amidines and Guanidines: Among non-acidic hypoglycemic agents, there are several intriguing guanidines and amidines. Pirogliride, although its structure is somewhat reminiscent of biguanides, is reported to have a different activity profile and mechanism of action.
N N N N CH3
Pirogliride Cetpiperalone is piperazine derivative related to cyclic guanidines and has the potency range of tolbutamide, is probably an insulin releaser.
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O NH N H N NH
Cetpieralone A series of alpha alkoxy amidines. Displayed hypoglycemic and nutiuretic activity in animals, but poor separation of activity from toxicity exhibited by these compounds prevented clinical studies.
H3CH2CO N N H
-Alkoxy amidines 11) Fatty acid Oxidation Inhibitors: Its use as orally effective hypoglycemic compounds has its roots in Randles glucose-fatty acid cycle first proposed in the 1960s. This hypothesis recognized the reciprocal relationship that exists between fat and carbohydrate metabolism. A reduction in fatty acid oxidation should enhance carbohydrate utilization and consequently lower blood glucose levels. 12) Carnitine Palmitoyl Transferase (CPT): Most inhibitors of this enzyme reported in the literature are long chain fattyacyl CoA analogues. The two most thoroughly characterized CPT inhibitors are TDGA (2tetradelylglycidate) and its methyl ester (MeTDGA) and POCA (chlorophenylpentyoxirane carboxylate).
CH3(CH2)13
COOH O
COOH O
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Cl
ANTI-DIABETIC AGENTS
Emeriamine is a carnitine analogue, which has significant hypoglycemic effects in fasted rats and several other animal models. Another novel compound, 2-(3methylcinnamylhydrazono) propionate (MCHP) apparently inhibits the translocation of long chain fattyacyl carnitines across the mitochondrial membrane but has little or no effect on either CPT or CPT .
CH
CH2
COOH
HC
CH2 CH3
MCHP
NH
CH3 COOH
13) Hydrazinopropionic Acids: Over 20 years ago, monoamine oxidase inhibitors of the hydrazine type were proposed as supplementary hypoglycemic agents for the treatment of diabetes mellitus. They found two hydrazine analogues, (2-phenylethylhydra-zino) and 2(cyclohexylethylhydrazino) propionic acids (PEHP and CHEHP, respectively), with increased hypoglycemic activity and reduced toxicity.
H2C
H2C NH
CH3 COOH
Both compounds at dose of between 145 and 800 mol / kg (30 and 170 mg / kg, respectively) significantly lowered blood glucose in 48 hours fasted guinea pigs, rats and hamster. Glucose lowering effects were also observed in 12 hr fasted diabetic mice.
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H2C
H2C NH
CH3 COOH
PEHP Another novel hypoglycemic agent AS-6, is derived from ascochlorin which was first discovered in the filter cake of the fermented broth of the fungus. Ascochytavivia Libert. AS-6, the 4-0-carboxymethylated derivative of ascochlorin, is a more potent hypoglycemic agent and is more readily absorbed.
OH OHC H3C Cl O CH2 COOH H3C CH3 CH3 O
AS-6 14) -Adrenergic agonist: The utility of -Adrenergic agonists as hypoglycemic agents has been surprising, since acute administration of isoproterenol (isoprenaline) or the more selective 2-agonist, terbuteline, caused deterioration in glycemic control in humans.
OH CH CH2 NH CH3 CH H2 C
COOCH3
BRL-26830 New -adrenergic agonists have been designed for their utility in treatment of obesity and NIDDM, as opposed to the traditional antiasthematic 2-agonists. A subset of -adrenergic receptors that dose not fall clearly in to either 1 or 2 has been described in rat brown adipose tissue. Selective activation of this receptor, by chronic administration of
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BRL-26830 to genetically obese (57 BL/6, ob/ob) mice, stimulated the metabolic activity of brown adipose tissue, elevated caloric consumption and resulted in a highly significant reduction in weight gain. A second -adrenergic agonist with potential utility in the improvement of insulin sensitivity is Ro-16-8714. When obese mice (C57BL/6J, ob/ob) received this agent for 15 days, glycosuria rapidly diminished and blood glucose was normalized, while circulating insulin levels were not altered.
OH CH CH OH CH2 N CH2 OH CH CH2 CH2 O NH2
Ro-16-8714 15) Anorectic agents: Weight loss in the treatment of obese NIDDM is often an effective means of achieving improved glycemic control. When diet therapy alone is inadequate to initiate the weight reduction program variety of anorectic agents are available for short-term therapy. Two of the agents, mazindol and fenfluramine, may also possess activities which improve glucose control independent of the weight loss they reduce.
OH CH CH OH CH2 N CH2 OH CH CH2 CH2 O NH2
Mazindol Ciclizindol, a drug structurally related to mazindole, also stimulated glucose uptake in to human skeletal muscle in both the presence and absence of insulin.
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Cl HO N
Ciclazindol Fenfluramine is an anorectic agent structurally similar to amphetamine, but with a mechanism of action relating to its 5-hydroxytryptamine- agonistic activity, which distinguishes a from the amphetamine class of drugs.
CH3 CH2 CF3 CH NH CH2 CH3
Fenfluramine 16) Steroids: Dehydroepiandrosterone (DHEA) is a major secretory product of the adrenal cortex, which ameliorates several metabolic abnormalities found in obese, insulin resistant rodents.40 Substantial improvement in glucose metabolism in insulin resistant rodents, has been demonstrated with chronic dosing of DHEA and its metabolites. Although DHEA produces pronounced changes in glucose metabolism and insulin sensitivity, three metabolic products of DHEA, 3-tetrahydroxyetiocholanolone (tetra-ET), 3-hydroxyetiocholano lone (Beta- ET), -hydroxyetiocholanolone (-ET) and DHEA sulfate, are more potent hypoglycemic agents.
O O
HO
HO
DHEA
3--hydroxyetiocholanolone
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HO
3--hydroxyetiocholanolon 17) Miscellaneous Agents: The anorectic agent fenfluramine has been shown to improve glucose tolerance and to lower fasting blood sugar in diabetes in numerous studies. A fenfluramine analogue, 780 SE has also been shown to improve tolerance in insulin-independent diabetics, Potential of insulin mediated glucose utilization in the periphery has also been postulated as the mechanism of action.
CH3 CH2 CF3 CH NH CH2 CH3
Fenfluramine
CH3 CH2 CF3 CH H CO
NHCH2CH2O
780 SE The hypoglycemic agent halofenate at a dose of 500-1500 mg daily reduces the requirements for sulfonylureas in diabetics, and this effect seems to be mediated by interference with the metabolism of the sulfonylurea and not by a direct hypoglycemic effect.
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CF3 Cl
NH COOH
Halofenate
COCH3
The hypoglycemic drug clofibrate on the other hand, which also transiently potentiates the effects of sulfonylureas at a dose of 1000 mg bid, has been shown to lower fasting and postprandial glucose in diabetics when given alone in a 7 day study, supposedly by increasing insulin sensitivity; however; it had no effect on fasting blood glucose in longer term (48 weeks) studies.
CH3 O Cl CH3 COOCH2CH3
Clofibrate Experiments in normal subjects suggested that the glycosidase and amylase inhibitor acarbose (BAY 5421, 60), used at about 75 mg, should be of value in decreasing postprandial blood glucose peaks.
HOCH2 HO HO OH NH
H3C O
HOCH2 O O
HOCH2 O O OH OH
HO
OH
HO
Acarbose
OH HO
A study in diabetics showed that addition of 6 times 50 mg of daily to the usual sulfonylurea or insulin regimen led to a further decrease in blood glucose values. Somatostatin a tetrapeptide which was originally isolated from hypothalamus, but which occurs also in the D-cell of the pancreas, suppresses the secretion of growth harmone, glucagons and insulin dependent diabetics, but caused only a transient hypoglycemia
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10 11
12 13 14
H-Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys-OH
2,4-Thiazolidinediones: A recent new class of oral hypoglycemic drugs thiazolidinediones was found to be effective against noninsulin dependent diabetes mellitus. Its development started many years ago and still a lot of work is left with this class of compounds. In 1980 Kawamatsu, Y.; Saraie, E. found that ethyl 2-chloro-3-[4-(2-methyl-2phenylpropoxy) phenyl] propionate (AL-294) was effective against hyperglycemia and hyperlipidemia in genetically obese and diabetic mice, yellow KK, which develop glucose and lipid dismetabolism associated with severe insulin resistance.
H C C COOCH2CH3 H2 Cl
In 1982 Shohda, Takashi.; Kawamatsu, Y. from Takeda Chemical Industries Ltd. Osaka, Japan developed a series of compounds containing 4-(2-methyl-2-phenylpropoxy) benzyl moity and evaluated their hypoglycemic and hypolipidemic activities with genetically obese and diabetic mice, yellow KK. Among these compounds 5-[4-(2-methyl2-phenylpropoxy) benzyl] thiazolidine-2, 4-dione (AL-321) was found to possess hypoglycemic and hypolipidemic activities higher than AL-294.
O NH O
AL-321
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In the same year more than 100 5-substituted thiazolidine-2, 4-dione were prepared and their hypoglycemic and hypolipidemic activities were evaluated with genetically obese and diabetic mice, yellow KK. Among these compounds 5-{4-[2-(3-pyridyl) ethoxy] benzyl} benzyl] thiazolidine-2, 4-dione (ADD-3878, ciglitazone) exhibited most favorable activity.
O H2 C CH3
ADD-3878 (Ciglitazone) In 1982 Shohda, T; Kawamatsu, Y. from Takeda Chemical Industries Ltd. and Senju Pharmaceutical Co., Ltd. Japan synthesized and evaluated thiazolidine-2, 4-dione having substitution at 5-position for Aldose Reductase Inhibitors. In 1984 Shohda, T; Kawamatsu, Y. of Takeda Chemical Industries Ltd. Osaka, synthesized compounds having hydroxy and an oxo moity on the cyclohexane ring of ciglitazone to clarify the structure of the metabolites of ciglitazone and for studies of their pharmacological properties. benzyl] Of the metabolites identified, exhibited 5-[4-(t-3-hydroxy-1extremely potent cyclohexylmethoxy) thiazolidine-2, 4-dione
NH O
R=
H2 C CH3
HO
H2 C CH3
HO
H2 C CH3
H2 C O CH3
4-oxo
cis-4-ol
trans-4-ol
3-oxo
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H2 C O CH3
H2 C HO CH3
H2 C OH CH 3
H2 C HO CH3
trans-3-ol
2-oxo
2-ol
cis3-ol
In 1986 Meguro, K; Fugita, T.; Shohda, T. of Takeda Chemical Industries Ltd. Osaka, Got a US patent (4,687,777) as well as European patent (0193256) for some thiazolidedione derivatives of formula given as (A) exhibited blood sugar and lipid lowering activity in mammals.
O C2H5 N O S NH O
(A) In 1989 Yoshioka, T.; Fujita, T; Kanai T. et al. at Sankyo Co., Ltd. Japan investigated series of hindered phenols hypolipidemic and/or hypoglycemic agents with ability to inhibit lipid peroxidation. Among the compounds of this series (f)-5-[4-[(6hydroxy-2, 5, 7, 8-tetramethylchroman-2-yl) methoxy]-benzyl]-2, 4-thiazolidinedione (CS-045) was found to have all of our expected properties and was selected as a candidate for further development as a hypoglycemic and hypolipidemic agent.
O HO O S O NH
Troglitazone (CS-045) In 1990 Zask, A.; McCaleb, M. L. of Wyeth-Ayerst Research, New Jersey synthesized a series of (naphthalenylsulfonyl)- 2, 4-thiazolidinedione and evaluated for antihyperglycemic activity in insulin-resistant, genetically diabetic db/db mouse model of non-insulin dependent diabetes mellitus (NIDDM). The best analogue (AY-31637) was equipotent to ciglitazone.
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O SO2 S NH O
(AY-31637) In 1991 Clark, D. A.; Goldstein, S. W of Central Research, Pfizer, Groton synthesized Dihydrobenopyran and dihydrobenzofuran thiazolidedione-2, 4-diones. These compounds represent conformationally restricted analogues of novel hypoglycemic ciglitazone. Among the compounds of this series englitazone (CP-68722, CP-72466) was proved to be efficacious in terms of activity.
O S O NH
Englitazone (CP-68722, CP-72466) In 1991 Ammos, Y; Shohda, T. synthesized various analogues of Pioglitazone (AD-4833, U-72107). Several 5[4-(2-(2-pyridyl) ethoxy] benzylidine]-2,4thiazolidinediones were equipotent to pioglitazone however; the thia analogues and benzylidine heterocycles had decreased activity.
O N O S O
Pioglitazone (AD-4833, U-72107) In 1992 Shohda, T.; Fugita. T. of Takeda Chemical Industries Ltd. Osaka, synthesized a series of 5- [4-(2-(2-pyridyl) ethoxy] benzylidine]-2, 4-thiazolidinediones as modification of the novel antidiabetic Pioglitazone (AD-4833, U-72107). Among the compounds synthesized 5- [4-(2-(5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzy]-2,4-
NH
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thiazolidinedione (B) exhibited the most potent activity, more than 100 times that of pioglitazone.
R1 N
R2 Y (CH2)n O
(B)
O NH O
In 1994 Barrie, C. C.; Thurlby, P. L. from SmithKline Beecham Pharmaceuticals, UK synthesized a series of [[-(Hetro cyclyl amino) alkoxy] benzyl 2,4thiazolidinedionesantihyperglycemic activity together with effects on hemoglobin content was performed in genetically obese C57 B1/6 ob/ob mice. From these studies BRL 49653 has been selected for further evaluation.
O CH3 N N O
BRL 49653 In 1998 Lohray, B. B.; Rajagopalan, R. of Dr. Reddys Research Foundation, Hyderabad, India synthesized a series of [[(heterocyclyl) ethoxy] benzyl]-2,4thiazolidinediones. Many of these compounds have shown superior euglycemic and hypolipidemic activity compared to troglitazone (CS045). The indole analogue DRF-2189 was found to be more potent insulin sensitizer, compared to BRL-49653 in genetically obese C57BL/6J-ob/ob and 57BL/KS-db/db mice.
NH O
O N NH O
DRF-2189
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In 1999 Lohray, B. B.; Rajagopalan, R. Dr. Reddys research foundation, Hyderabad, India synthesized substituted pyridyl- and quinolinyl-containing 2, 4thiazolidinediones having cyclic amine as a linker and evaluated hypoglycemic and hypolipidemic activity and compared with BRL-49653. Among all the salts evaluated, the maleate salt of unsaturated TZD (5a) was found to be euglycemic and hypolipidemic compound.
N O S
O NH O
(5a) In 1999 Nomura, M.; Miyachi, H. of Kyorin Pharmaceutical Company, Japan prepared a series of (3-substituted benzyl) thiazolidine-2, 4-dione which led to the identification of (KRP-297) as a candidate for the treatment of diabetes mellitus.
O CH2 CF3 H CH3O
CH2 S NH O O
KRP-297 In 2000 Oguchi, M.; Fugita, T. of Sankyo company, Ltd., and sankyo pharma research institute, California designed and synthesized a series of Imidazopyridine thiazolidine-2, 4-diones and evaluated for its effect on Insulin induced 3T3-L1 adipocyte differentiation invitro and its hypoglycemic activity in genetically diabetic KK mouse in vivo.
R4 R3 R2 N N R1 N O S NH O
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R1= H, Me, Et, Ph, 4-Cl-C6H4CH2, R2= H, Me, Cl, OH, etc R3= H, Cl, Br, CF3, R4= = H, Me In 2003 Desai, R. C.; Berger, J. P.; Kwan, L. of Merck Research Laboratories, USA synthesized a number of potent 5-aryl thiazolidine-2, 4-diones and performed efficacy studies which showed them superior to rosiglitazone in correcting hyperglycemia and hypertriglyceridemia.
O O O S O NH O
5-aryl thiazolidine-2, 4-diones In 2004 Bhatt, A. B.; Srivastava, A. K. from CDRI, Lucknow synthesized a number of thiazolidinedione derivatives having carboxylic ester appendage at N-3 and evaluated their hypoglycemic activity. N-carboalkoxymethylthiazolidine-2, 4-diones was selected as core structure with substituted benzylidine and benzyl and heteroaryl derivatives.
O OX
N O
N-carboalkoxymethylthiazolidine-2, 4-diones R=C6H5OH, C6H5CF3, C6H5CH3, C6H5Cl etc. X=CH2CH3, CH3 Z=Single Bond, Double Bond Iqbal, Javed. of Dr. Reddys Laboratories, Hyderabad, India designed TZD derivatives, which can reduce plasma glucose with less adipogenesis. The SAR of these TZD derivatives gave Balaglitazone which has 70% of PPAR- transactivation compared to rosiglitazone and showed partial agonism in competitive binding assay. Balaglitazone has
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shown good efficacy in db/db and ob/ob mice models at 3mg/kg. In zucker fa/fa rats it shows insulin sensitization effects by 70% reduction in insulin and 80% reduction in free fatty acids at 3mg/kg dose. Balaglitazone is now in phase-II clinical trials. The literature, found for this class of drugs shows that there is a lot of advancement in the development of a novel analogues of thiazolidinedione for the treatment of noninsulin dependent diabetes mellitus and it is also clear that there has been abundant research activity in this field globally. Several approaches have been attempted and some new approaches are still emerging.
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3. CLASSIFICATION
1. Insulin 2. Secretagogues 2.1. Sulfonylureas 2.2. Meglitinides 3. Sensitizers 3.1. Biguanides 3.2. Thiazolidinediones 4. Alpha-glucosidase inhibitors 5. Peptide analogs 5.1. Incretin mimetics 5.1.1. Glucagon-like peptide (GLP) analogs and agonists 5.1.2. Gastric inhibitory peptide (GIP) analogs 5.1.3. Protein Tyrosin Phosphate 1 inhibitors 5.2. DPP-4 inhibitors 5.3. Amylin analogues
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Sensitizers
TZDs (PPAR)
Insulin
Secretagogues
Dual PPAR Aleglitazar Muraglitazar Tesaglitazar agonists 1stgeneration: Acetohexamide Carbutamide Chlorpropamide Gliclazide Tolbutamide Tolazamide K+ ATP Sulfonylureas 2nd generation: Glibenclamide ( Glyburide) Glipizide Gliquidone Glyclopyramide 3rd generation: Glimepiride Meglitinides/ Glinides GLP-1 analogs Nateglinide Repaglinide Mitiglinide
Alogliptin Linagliptin Saxagliptin Sitagliptin DPP-4 Vildagliptin inhibitors . fast acting : (Insulin lispro Insulin aspart Insulin glulisine) Short acting : (Regular insulin) long acting : (Insulin glargine Insulin detemir) Inhalable insulin (Exubera) NPH insulin Acarbose Miglitol Voglibose
Other
SGLT2 inhibitor Other
Phase III.
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4. INSULIN
Sanger (in 1950s) put forward the primary structure of insulin as below in Figure.
20 20
Figure 4.1 Primary structure of proinsulin, depicting cleavage sites to produce insulin. The above Figure has the following Salient Features, namely: (1) Proinsulin is the immediate precursor to insulin in the single-chain peptide. (2) Proinsulin folds to adopt the correct orientation of the prevailing disulphide bonds plus other relevant conformational constraints whatsoever on account of its primary structure exclusively. (3) Proinsulin in reality, has a precursor of its own, preproinsulina peptide, that essentially comprises of hundreds of additional residues. (4) At an emerging critical situation the insulin gets generated from proinsulin due to the ensuing cleavage of proinsulin at the two points indicated. This eventually produces
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insulin, that comprises of a 21-residue A chain and strategically linked with two disulphide bonds ultimately to a 30-residue B chain. Interestingly, these bondages between the two aforesaid residual chains A and B are invariably oriented almost perfectly and correctly by virtue of the prempted nature of proinsulin folding.
4.1 Description
Insulin is a hormone produced by the beta cells in the islets of Langerhans in the pancreas.
Figure 4.2 Insuline structure Insulin is used medically to treat some forms of diabetes mellitus. By reducing the concentration of glucose in the blood, insulin is thought to prevent or reduce the long-term complications of diabetes, including damage to the blood vessels, eyes, kidneys, and nerves.
ANTI-DIABETIC AGENTS
plasma half-life that stands at nearly 9 minutes. Importantly, the duration of action is not linearly proportional to the size of the dose, but it is a simple function of the logarithm of the dose i.e., if 1 unit exerts its action for 4 hours then 10 units will last 8 hours. In usual practice the duration is from 8 to 12 hour after the subcutaneous injection, which is particularly timed a few minutes before the ingestion of food so as to avoid any possible untoward fall in the prevailing blood-glucose level.
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4.2.3.1 Mechanism of Action It has been duly observed that the amorphous zinc-insulin component exerts a duration of action ranging between 68 hours, whereas the crystalline zinc-insulin component a duration of action more than 36 hour, certainly due to the sluggishness and slowness with which the larger crystals get dissolved. However, an appropriate dosage of the 3 : 7 mixture employed usually displays an onset of action of 1 to 2.5 hour and an intermediate duration of action which is very near to that of isophane insulin suspension (24 hour), with which preparation this drug could be employed interchangeably without any problem whatsoever. However, it must not be administered IV. The major advantage of zinc insulin is its absolute freedom from foreign proteinous matter, such as : globin, or protamine, to which certain subjects are sensitive.
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4.2.5.2 Mechanism of Action The zinc-insulin in this particular form is a mixture of amorphous and extremely fine crystalline materials. As a result, the drug serves as a rapid-acting insulin with an onset of 1 to 1.5 hour, an attainable peak of 5-10 hours, and a duration of action ranging between 12-16 hours. 4.2.5.3 Note: Since this specific form of insulin is essentially free of any foreign proteins, the incidence of allergic reactions is found to be extremely low.
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4.2.7.2 Mechanism of Action The drug exerts a long-acting action having an onset of action of 4 to 8 hour, a peak at 14 to 24 hour, and a duration of action nearly 36 hour. As a result this drug need not be administered with any definite time relation frame to the corresponding food intake. Besides, it should not be depended upon solely when a very prompt action is required, such as : in diabetic acidosis and coma. Since the drug possesses an inherent prolonged action, it must not be administered more frequently than once a day. It has been duly observed that low levels invariably persists for 3 o 4 days; and, therefore, the dose must be adjusted at intervals of not less than 3 days. It is given by injection, normally into the loose subcutaneous tissue. 4.2.7.3 Note: The drug should never be administered IV.
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5. Secretagogues
5.1 K+ ATP 5.1.1 Sulfonylureas
The sulfonylurea hypoglycemic agents are basically sulphonamide structural analogues but they do not essentially possess any antibacterial activity whatsoever. In fact, out of 12,000 sulfonylureas have been synthesized and clinically screened, and approximately 10 compounds are being used currently across the globe for lowering blood-sugar levels significantly and safely. The sulfonylureas may be represented by the following s
Salient Features: The salient features of the sulfonylureas are as given below : (1) These are urea derivatives having an arylsulfonyl moiety in the 1 position and an aliphatic function at the 3-position. (2) The aliphatic moiety, R, essentially confers lipophilic characteristic properties to the newer drug molecule. (3) Optimal therapeutic activity often results when R comprises of 3 to 6 carbon atoms, as in acetohexamide, chlorpropamide and tolbutamide. (4) Aryl functional moieties at R invariably give rise to toxic compounds. (5) The R moiety strategically positioned on the aromatic ring is primarily responsible for the duration of action of the compound. 5.1.1.1 SAR of Sulfonylureas Certain substituents when placed at para position in benzene ring tend to potentiate the activity, e.g. halogens, amino, acetyl, methyl, methylthio and trifluoromethyl groups.
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The size of terminal nitrogen along with its aliphatic subsituent R, determines lipophilic properties of the molecules. Optimum activity results when R consists of 3 to 6 carbon atoms. The nature of para subsituents in benzene ring (-x-) appears to govern the duration of action of the compound. Aliphatic subsituents (R) at the terminal nitrogen may also be replaced by an alicyclic and hetrocyclic ring. hypoglycemic activity can be related to the nature of sulfonyl grouping. Replacement of a metabolically easily oxidize group, like a CH3 group by a less readily oxidize chlorine was used to transform the short actingtolbutamide into long acting chlorpropamide, with a half life six fold greater than its parent. However, these agents are now divided into two sub-groups, namely: (a) 1st generation sulfonylureas (b) 2nd generation sulfonylureas These two aforesaid classes of sulfonylureas will be further separated by: First-generation agents o tolbutamide (Orinase) o acetohexamide (Dymelor) o tolazamide (Tolinase) o chlorpropamide (Diabinese) Second-generation agents o glipizide (Glucotrol) o glyburide (Diabeta, Micronase, Glynase) o glimepiride (Amaryl) o gliclazide (Diamicron)
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Tolbutamide
Structure
Systemic (IUPAC) Name N-[(butylamino)carbonyl]-4-methylbenzenesulfonamide Chemical data FORMULA MOLECULAR MASS Pharmacokinetic data METABOLISM PROTEIN BINDING HALF LIFE EXECRETION
Hepatic (CYP2C19-mediated)
Tolbutamide is a first generation potassium channel blocker, sulfonylurea oral hypoglycemic drug sold under the brand name Orinase. This drug may be used in the management of type II diabetes if diet alone is not effective. Tolbutamide stimulates the secretion of insulin by the pancreas. Since the pancreas must synthesize insulin in order for this drug to work, it is not effective in the management of type I diabetes. It is not routinely used due to a higher incidence of adverse effects compared to newer second generation sulfonylureas, such as glyburide.
Mechanism of Action
The drug usually follows the major route of breakdown ultimately leading to the formation of butylamine and p-toluene sulphonamide respectively. Importantly, the observed hypoglycemia induced by rather higher doses of the drug is mostly not as severe and acute as can be induced by insulin; and, therefore, the chances of severe hypoglycemic reactions is quite lower with tolbutamide ; however, one may observe acute refractory hypoglycemia occasionally does take place. In other words, refractoriness to it often develops.
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Side Effects
1. Hypoglycemia 2. Weight gain 3. Hypersensitivity- Cross-allergicity with sulfonamide 4. Drug Interactions (especially first generation drugs): Increase Hypoglycemia with cimetidine, Insulin, salicylates, sulfonamides.
Synthesis of Tolbutamide
Procedure First of all toluene is treated with chlorosulfonic acid to yield p-toluenesulphonyl chloride, which on treatment with ammonia gives rise to the formation of ptoluenesulphonamide. The resulting product on condensation with ethyl chloroformate in the presence of pyridine produces N-p-toluenesulphonyl carbamate with the loss of a mole of HCl. Further aminolysis of this product with butyl amine using ethylene glycol monomethyl ether as a reaction medium loses a mole of ethanol and yields tolbutamide. It is mostly beneficial in the treatment of selected cases of non-insulin-dependent diabetes melitus (NIDDM). Interestingly, only such patients having some residual functional islet -cells which may be stimulated by this drug shall afford a positive response. Therefore, it
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is quite obvious that such subjects who essentially need more than 40 Units of insulin per day normally will not respond to this drug.
Acetohexamide
Structure
Systemic (IUPAC) Name 4-acetyl-N-(cyclohexylcarbamoyl)benzenesulfonamide Chemical data FORMULA MOLECULAR MASS PROTEIN BINDING
90 %
It lowers the blood-sugar level particularly by causing stimulation for the release of endogenous insulin.
Mechanism of Action
The drug gets metabolized in the liver solely to a reduced entity, the corresponding -hydroxymethyl structural analogue, which is present predominantly in humans, shares the prime responsibility for the ensuing hypoglycemic activity.
Synthesis of Acetohexamide
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SAR of Acetohexamide
It is found to be an intermediate between tolbutamide and chlorpropamide i.e., in the former the cyclohexyl ring is replaced by butyl moiety and p-acetyl group with methyl group ; while in the latter the cyclohexyl group is replaced by propyl moiety and the p-acetyl function with chloro moiety. Acetohexamide is metabolized in the liver to a reduced from, the -hydroxyethyl derivative. This metabolite, the main one in human, possesses hypoglycemic activity. Acetohexamide is intermediate between tolbutamide and chlorpropamide in potency and duration of effect on blood sugar level.
Tolazamide
Structure
Systemic (IUPAC) Name N-[(azepan-1-ylamino)carbonyl]-4-methylbenzenesulfonamide Chemical data FORMULA MOLECULAR MASS Pharmacokinetic data HALF LIFE EXECRETION
7 hours
Renal (85%) and fecal (7%)
Mechanism of Action
Based on the radiactive studies it has been observed that nearly 85% of an oral dose usually appears in the urine as its corresponding metabolites which were certainly more water-soluble than the parent tolazamide itself.
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Synthesis of Tolazamide
Chlorpropamide
Structure
Systemic (IUPAC) Name 1-[(p-Chlorophenyl)-Sulphonyl]-3-propyl urea Chemical data FORMULA MOLECULAR MASS HALF LIFE
36 hours
Chlorpropamide is a drug in the sulphonylurea class used to treat type 2 diabetes mellitus. It is a long-acting sulphonylurea. It has more side effects than other sulphonylureas and its use is no longer recommended.
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Synthesis of Chlorpropamide
Procedure The interaction between p-chlorobenzenesulphonamide and phenyl isocyanate in equimolar concentrations under the influence of heat undergoes addition reaction to yield the desired official compound. The therapeutic application of this drug is limited to such subjects having a history of table, mild to mderately severe diabetes melitus who still retain residual pancreatic cell function to a certain extent.
Mechanism of Action
The drug is found to be more resistant to conversion to its corresponding inactive metabolites than is tolbutamide; and, therefore, it exhibits a much longer duration of action. It has also been reported that almost 50% of the drug gets usually excreted as metabolites, with the principal one being hydroxylated at the C-2 position of the propylside chain.
Glipizide
STRUCTURE
Systemic (IUPAC) Name N-(4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenethyl)-5- methylpyrazine-2-carboxamide Chemical data FORMULA MOLECULAR MASS Pharmacokinetic data C21H27N5O4S 445.536 g/mol
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BIOAVAIBILITY PROTEIN BINDING METABOLISM HALF LIFE EXECRETION ROUTE 100% (regular formulation),90% (extended release) 98 -99 % Hepatic hydroxylation 2 to 4 hr Renal and fecal Oral
Glipizide is an oral medium-to-long acting anti-diabetic drug from the sulfonylurea class. It is classified as a second generation sulfonylurea, which means that it undergoes enterohepatic circulation. The structure on the R2 group is a much larger cyclo or aromatic group compared to the 1st generation sulfonylureas. This leads to a once a day dosing that is much less than the first generation, about 100 fold.
Mechanism of Action
The primary hypoglycemic action of this drug is caused due to the fact that it upregulates the insulin receptors in the periphery. It is also believed that it does not exert a direct effect on glucagon secretion. The drug gets metabolized via oxidation of the cyclohexane ring to the corresponding p-hydroxy and m-hydroxy metabolites. Besides, a minor metabolite which occurs invariably essentially involves the N-acetyl structural analogue that eventually results, from the acetylation of the primary amine caused due to the hydrolysis of the amide system exclusively by amidase enzymes. Synthesis of Glipizide
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Procedure Glipizide may be prepared by the condensation of 4-[2-(5-methyl-2-pyrazinecarboxamido)-ethyl] benzenesulphonamide with cyclohexylisocyanate in equimolar proportions. It is employed for the treatment of Type 2 diabetes mellitus which is found to be 100 folds more potent than tolbutamide in evoking the pancreatic secretion of insulin. It essentially differs from other oral hypoglycemic drugs wherein the ensuing tolerance to this specific action evidently does not take place. Note : The drug enjoys two special status, namely: (a) Treatment of non-insulin dependent diabetes mellitus (NIDDM) since it is effective in most patients who particularly show resistance to all other hypoglycemic drugs ; (b) Differs from other oral hypoglycemic drug because it is found to be more effective during eating than during fasting.
Gliclazide
Structure
Gliclazide is an oral hypoglycemic (anti-diabetic drug) and is classified as a sulfonylurea. SAR of Gliclazide Gliclazide is very similar to tolbutamide, with the exception of the bicyclic hetrocyclic ring found in gliclazide. The pyrrolidine increases its lipophilicity over that of tolbutamide, which increases its half life. Even so, the p-methyl is susceptible to the same
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oxidative metabolic fate as observed for tolbutamide, namely, it will be metabolized to a carboxylic acid.
Synthesis of Gliclazide
Glimepiride
Structure
Systemic (IUPAC) Name 3-ethyl-4-methyl-N-(4-[N-((1r,4r)-4-methylcyclohexylcarbamoyl)sulfamoyl]phenethyl)-2-oxo-2,5-dihydro1H-pyrrole-1-carboxamide Chemical data FORMULA MOLECULAR MASS Pharmacokinetic data PROTEIN BINDING HALF LIFE EXECRETION ROUTES
ANTI-DIABETIC AGENTS
Mechanism of Action The drug is found to be metabolized primarily through oxidation of the alkyl side chain attached to the pyrrolidine nucleus via a minor metabolic path that essentially involves acetylation of the amine function.
Synthesis of Glimepiride
SAR of Glimepiride The only major distinct difference between this drug and glipizide is that the former contains a five-membered pyrrolidine ring whereas the latter contains a sixmembered pyrazine ring. It is metabolise primarily through oxidation of the alkyl side chain of the pyrrolidine, with a minor metabolic route involving acetylation of the amine.
Glibenclamide
Structure
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Systemic (IUPAC) Name 5-chloro-N-(4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenethyl)-2-methoxybenzamide Chemical data FORMULA MOLECULAR MASS Pharmacokinetic data PROTEIN BINDING METABOLISM HALF LIFE EXECRETION ROUTES
Extensive
Hepatic hydroxylation (CYP2C9-mediated)
Glibenclamide (INN), also known as glyburide (USAN), is an anti-diabetic drug in a class of medications known as sulfonylureas. It is mostly used for Type 2 diabetes melitus. It is found to be almost 200 times as potent as tolbutamide in evoking the release of insulin from the pancreatic islets. However, it exerts a rather more effective agent in causing suppression of fasting than postprandial hyperglycemia. Synthesis of Glibenclamide
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SAR of Glyburide The SAR of Glyburide and Glypizzide are discussed below :
Potency Compared to Tolbutamide 100 times more potent 200 times more potent
Obviously the presence of R in glyburide potentiates the hypoglycemic activity 200 times, whereas the heterocylic nucleus in glipizide potentiates 100 times in comparison to tolbutamide. It is 2nd generation oral hypoglycemic agent. The drug has a half life elimination of 10 hours, but its hypoglycemic effects remains for up to 24 hours. Mechanism of Action The drug gets absorbed upto 90% when administered orally from an empty stomach. About 97% gets bound to plasma albumin in the form of a weak-acid anion; and therefore, is found to be more susceptible to displacement by a host of weakly acidic drug substances. Elimination is mostly afforded by hepatic metabolism. The half-life ranges between 1.5 to 5 hours, and the duration of action lasts upto 24 hours.
5.1.2 Meglitinide
Metaglinides are nothing but non sulphonylurea oral hypoglucemic agents normally employed in the control and management of type 2 diabetes (i.e, non-insulindependent diabetes mellitus, NIDDM). Interestingly, these agents have a tendency to show up a quick and rapid onset and a short duration of action. Just like the sulphonylureas, they also exert their action by inducing insulinrelease from the prevailing functional
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pancreatic -cells. Importantly the mechanism of action of the metaglinides is observed to differ from that of the sulphonylureas. In fact, the mechanism of action could be explained as under: (a) Through binding to the particular receptors in the -cells membrane that ultimately lead to the closure of ATP-dependent K+ channels, and (b) K+ channel blockade affords depolarizes the -cell membrane, which iN turn gives rise to Ca2+ influx, enhanced intracellular Ca2+, and finally stimulation of insulin secretion. Based on the altogether different mechanism of action from the two aforesaid sulphonylureas there exist two distinct, major and spectacular existing differences between these two apparently similar categories of drug substances, namely :
(ii) Metaglinides do not exert a prolonged duration of action as those exhibited by the
sulphonylureas. Its effect lasts for less than 1 hour whereas sulphonylureas continue to cause insulin generation for several hours.
Repaglinide
Structure
Systemic (IUPAC) Name (S)-(+)-2-ethoxy-4-[2-(3-methyl-1-[2-(piperidin-1-yl)phenyl]butylamino)-2-oxoethyl]benzoic acid Chemical data FORMULA MOLECULAR MASS Pharmacokinetic data BIOAVAIBILITY PROTEIN BINDING
ANTI-DIABETIC AGENTS
METABOLISM HALF LIFE EXECRETION ROUTES Hepatic oxidation and glucuronidation (CYP3A4mediated)
1 hr
Fecal (90%) and renal (8%)
Oral
It is used in the control and management of Type-2 diabetes mellitus. It must be taken along with meals. Mechanism of Action The drug is found to exert its action by stimulating insulin secretion by binding to and inhibiting the ATP-dependent K+ channels in the -cell membrane, resulting ultimately in an opening of Ca+2 channels. It gets absorbed more or less rapidly and completely from the GI tract; and also is exhaustively metabolized in the liver by two biochemical phenomena, such as: (a) Glucuronidation; and (b) Oxidative biotransformation. Besides, it has been established that the hepatic cytochrome P-450 system 3A4 is predominantly involved in the ultimate metabolism of repaglinide. SAR of Repaglinide Repaglinide represents a new class of nonsulfonylurea oral hypoglycemic agent. With a fast onset and short duration of action, the medication should be taken with meals. It is oxidized by CYP 3A4, and the carboxylic acid may be conjugated to inactive compounds. Less than 0.2 % is excreated unchanged by kidney, which may be an adventage for elderly patients who are renally impaired.
Side effects
The most common side effects involves hypoglycemia, resulting in headache, cold sweats, anxity, and changes in mental state.
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Nateglinide
Structure
Systemic (IUPAC) Name (R)-2-(4-isopropylcyclohexanecarboxamido)-3-phenylpropanoic acid Chemical data FORMULA MOLECULAR MASS Pharmacokinetic data PROTEIN BINDING HALF LIFE
98 % 1.5 hr
Nateglinide (INN, trade name Starlix) is a drug for the treatment of type 2 diabetes. Nateglinide was developed by the Swiss pharmaceutical company Novartis. Nateglinide belongs to the meglitinide class of blood glucose-lowering drugs.
Dosage
Nateglinide is delivered in 60mg & 120mg tablet form.
5.2.1 Glucagon-like peptide-1 hormons It is the incretin hormone acting via GLP-1 receptor (a G-protein coupled receptor). When blood glucose levels are high this hormone stimulates insulin secretion and biosynthesis and inhibits glucagon release leading to reduce hepatic glucose output. In addition it serves as an ileal brake, slowing gastric emptying and reducing appetite. GLP-1 has a no. of effects on regulation of -cell mass: stimulation of replication and growth and inhibition of apoptosis of existing -cells and neogenesis of new -cells from
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precursors. Thus, GLP-1 therapy for the treatment of type 2 diabetes is an area of active research. There are two sub-classes of GLP-1 in clinical development .One is natural GLP-1 and the other is exendin-4, a peptide agonist isolated from the venom of lizard and is more potent than natural GLP-1. Exenatide (AC2993) is a peptide consist of 39 amino acid approved recently developed by Lilly and Amylin & used for treatment of diabetes. Liraglutide (NN2211), is under phase clinical trial by Novo Nordisk, CJC1131 is under phase I / clinical trial by Conjuchem, ZP10 is under phase I / clinical trial by Zealand. Glucagon-like peptide-1 analogs are a new class of drug for treatment of type 2 diabetes. One of their advantages is that they have a lower risk of causing hypoglycemia.
Exenatide
Structure
Chemical data FORMULA Pharmacokinetic data METABOLISM HALF LIFE EXECRETION ROUTES
C184H282N50O60S Proteolysis
2.4 hr
renal/proteolysis subcutaneous injection
Exenatide (INN, marketed as Byetta) is one of a new class of medications (incretin mimetics) approved (Apr 2005) for the treatment of diabetes mellitus type 2. (It is not approved for use in diabetes mellitus type 1). It is manufactured by Eli Lilly and Company. Exenatide is administered as a subcutaneous injection (under the skin) of the abdomen, thigh, or arm, 30 to 60 minutes before the first and last meal of the day.
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Albiglutide
Albiglutide is a drug under investigation by GlaxoSmithKline for treatment of type 2 diabetes. It is a dipeptidyl peptidase-4-resistant glucagon-like peptide-1 dimer fused to human albumin. It has a half life of 6 to 7 days (longer than exenatide or liraglutide).
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keynegative regulator of insulin signal transduction and a potential therapeutic target in the treatment of NIDDM and obesity.
ANTI-DIABETIC AGENTS
Red:Catalytic site ,(His214-Arg221); Blue: second aryl phosphate binding site Yellow :( Tyr46-Arg47-Asp48) , Magenta: (Asp181 and Phe182) Fig.5.3: Structure of PTP-1 showing main sites
The active site of PTP-1 contains a common structural motif HisCysSerAla GlyIleGlyArg, forming a rigid, cradle like structure that coordinates to the aryl phosphate moiety of the substrate. It contains an active site nucleophile, Cys 215. It also contain second aryl phosphate binding site. In the above structure, red is main catalytic active site which is from His 214 Arg 221, in the blue is contain second aryl phosphate binding site, in the yellow is YRD loop which play an important role in substrate binding, and in the magenta is Wpd loop which contain Asp181 & Phe 182 which is full of water and responsible for hydrogen bonding interactions. The dephosphorylation of tyrosine takes place via two steps. In the first step there is a nucleophilic attack on the substrate phosphate by the sulphur atom of Cys, coupled with protonation of tyrosyl leaving group by Asp181 acting as a general acid. This leads to the formation of cysteinyl phosphate intermediate. The second step mediated by Glu262 and Asp181, leads to the hydrolysis of catalytic intermediate and release of phosphate.
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PTP-1 has been closely structurally correlated with other members of PTP family especially TC-PTP. PTP-1 causes simultaneous dephosphorylation of phosphorylated 1162 & 1163 residue of insulin receptor thus causing inhibition of insulin signalling while other PTP s does not causes simultaneous dephosphorylation thus has important role in insulin signaling.
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ANTI-DIABETIC AGENTS
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Despite good biological target validation, designing PTP-1 inhibitors as oral agent is challenging because of the highly charged nature of the catalytic domain of the target. Furthermore the development of selective, potent and bioavailable inhibitors of PTP-1 will be a formidable challenge although some of the groundwork has now been laid out.
Figure No.5.5 Dipeptidyl peptidase-4 inhibitor The role of DPP-4, GLP-1 in glucose homeostasis. Following meal ingestion, the incretin hormones, intact (active) GLP-1 and GIP, released from gut endocrine cells and
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function to lower blood glucose levels by stimulating glucose-dependent insulin release from pancreatic -cells (GLP-1 and GIP) and suppressing glucose-dependent glucagon release from pancreatic -cells (GLP-1). However, once released into the circulation, incretin hormones are rapidly inactivated and degraded by plasma protease enzyme DPP4. DPP-4 inhibitors like sitagliptin inhibit breakdown of incretin hormones, thereby increasing active GLP-1 and GIP levels and promoting fasting and postprandial glycemic control. 5.4.1 Examples Drugs belonging to this class are:
sitagliptin (FDA approved 2006, marketed by Merck & Co. under the trade name Januvia), vildagliptin (marketed in the EU by Novartis under the trade name Galvus), Saxagliptin (being developed by Bristol-Myers Squibb, AstraZeneca and Otsuka Pharmaceutical Co.), linagliptin (being developed by Boehringer Ingelheim), Alogliptin (developed by Takeda Pharmaceutical Company, whose FDA application for the product is currently suspended as of June 2009).
Berberine, the common herbal dietery supplement, too inhibits dipeptidyl peptidase-4, which at least partly explains its anti-hyperglycemic activities. 5.4.2 Possible cancer risk Although extensive long-term, pre-clinical studies of the major DPP-4 inhibitors has failed to show any evidence of potential to cause tumors in laboratory animals, there was one in-vitro (i.e., test tube) study that has raised some questions. In theory, DPP-4 inhibitors may allow some cancers to progress, since DPP-4 appears to work as a suppressor in the development of cancer and tumours.
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Alogliptin
Structure
Systemic (IUPAC) Name 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile Chemical data FORMULA MOLECULAR MASS ROUTES
C18H21N5O2
339.39 g/mol
Oral
Alogliptin (codenamed SYR-322) is an investigational anti-diabetic drug in the DPP-4 inhibitor class, being developed by Takeda Pharmaceutical Company. Takeda has submitted a New Drug Application for alogliptin to the U.S. Food and Drug Administration, after positive results from Phase III clinical trials.FDA submission suspended or withdrawn June 2009 needing more data.
Linagliptin
Structure
Systemic (IUPAC) Name 8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3- methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7dihydro-1H-purine-2,6-dione Chemical data FORMULA MOLECULAR MASS ROUTES
C25H26N8O2
472.54 g/mol Oral
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Linagliptin (BI-1356, expected trade name Ondero) is a DPP-4 inhibitor developed by Boehringer Ingelheim undergoing research for type II diabetes. It is currently in a Phase III clinical trial.
Saxagliptin
Structure
Systemic (IUPAC) Name (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile Chemical data FORMULA MOLECULAR MASS
C18H25N3O2
315.41 g/mol
Saxagliptin (rINN), previously identified as BMS-477118, is a new oral hypoglycemic (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. It was developed by Bristol-Myers Squibb. In June 2008, it was announced that Onglyza would be the trade name under which saxagliptin will be marketed. The FDA approved Onglyza on July 31, 2009. Dipeptidyl peptidase-4's role in blood glucose regulation is thought to be through degradation of GIP and the degradation of GLP-1. Bristol-Myers Squibb announced on 27 December 2006 that Otsuka Pharmaceutical Co. has been granted exclusive rights to develop and commercialize the compound in Japan. Under the licensing agreement, Otsuka will be responsible for all development costs, but Bristol-Myers Squibb retains rights to co-promote saxagliptin with Otsuka in Japan. Further, on 11 January 2007 it was announced that Bristol-Myers Squibb and AstraZeneca would work together to complete development of the drug and in subsequent marketing.
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Sitagliptin
Structure
Systemic (IUPAC) Name (R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5trifluorophenyl)butan-2-amine Chemical data FORMULA MOLECULAR MASS Pharmacokinetic data BIOAVAIBILITY PROTEIN BINDING METABOLISM HALF LIFE EXECRETION ROUTES
C16H15F6N5O
407.314 g/mol
87 % 38 %
Hepatic (CYP3A4- and CYP2C8-mediated)
8 to 14 hour
Renal (80%)
Oral
Sitagliptin (INN; previously identified as MK-0431, trade name Januvia) is an oral antihyperglycemic (anti-diabetic drug) of the dipeptidyl peptidase-4 (DPP-4) inhibitor class, Sitagliptin being the only second generation DPP-4 inhibitor currently available in the USA. This enzyme-inhibiting drug is used either alone or in combination with other oral antihyperglycemic agents (such as metformin or a thiazolidinedione) for treatment of diabetes mellitus type 2. The benefit of this medicine is its lower side-effects (e.g., less hypoglycemia, less weight gain) in the control of blood glucose values. Exenatide (Byetta) also works by its effect on the incretin system.
Mechanism of Action
Sitagliptin works to competitively inhibit the enzyme dipeptidyl peptidase 4 (DPP4). This enzyme breaks down the incretins GLP-1 and GIP, gastrointestinal hormones that are released in response to a meal. By preventing GLP-1 and GIP inactivation, GLP-1 and
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GIP are able to potentiate the secretion of insulin and suppress the release of glucagon by the pancreas. This drives blood glucose levels towards normal. As the blood glucose level approaches normal, the amounts of insulin released and glucagon suppressed diminishes thus tending to prevent an "overshoot" and subsequent low blood sugar (hypoglycemia) which is seen with some other oral hypoglycemic agents.
Vildagliptin
Systemic (IUPAC) Name (S)-1-[N-(3-hydroxy-1-adamantyl)glycyl]pyrrolidine-2-carbonitrile Chemical data FORMULA MOLECULAR MASS SYNONYMS Pharmacokinetic data BIOAVAIBILITY PROTEIN BINDING METABOLISM
C17H25N3O2
303.399 g/mol
(2S)-1-{2-[(3-hydroxy-1adamantyl)amino]acetyl}pyrrolidine-2-carbonitrile
85 % 9.3 %
Mainly hydrolysis to inactive metabolite; CYP450 not appreciably involved
2 to 3 hr Renal Oral
Vildagliptin (previously identified as LAF237, trade name Galvus) is a new oral anti-hyperglycemic agent (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. Vildagliptin inhibits the inactivation of GLP-1 and GIP by DPP-4, allowing GLP-1 and GIP to potentiate the secretion of insulin in the beta cells and suppress glucagon release by the alpha cells of the islets of Langerhans in the pancreas. Vildagliptin has been shown to reduce hyperglycemia in type 2 diabetes mellitus. Novartis has since withdrawn its intent to submit vildagliptin to the FDA, as of July 2008. The Food and Drug Administration had demanded additional clinical data before it could approve vildagliptin including extra evidence that skin lesions and kidney impairment seen during an early study on animals have not occurred in human trials.
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6. Sensitizers
6.1 Biguanide
Structure
Systemic (IUPAC) Name Diguanide, 2-carbamimidoylguanidine Chemical data FORMULA MOLECULAR MASS
C2H7N5
101.11 g/mol
Biguanide can refer to a molecule, or to a class of drugs based upon this molecule. Biguanides can function as oral antihyperglycemic drugs used for diabetes mellitus or prediabetes treatment. They are also used as antimalarial drugs. The disinfectant polyaminopropyl biguanide (PAPB) features biguanide functional groups. 6.1.2 Examples of biguanides:
Metformin - widely used in treatment of diabetes mellitus type 2 Phenformin - withdrawn from the market in most countries due to toxic effects Buformin - withdrawn from the market due to toxic effects
6.1.3 Mechanism of action The mechanism of action of biguanides is not fully understood. However, in hyperinsulinemia, biguanides can lower fasting levels of insulin in plasma. Their therapeutic uses derive from their tendency to reduce gluconeogenesis in the liver, and, as a result, reduce the level of glucose in the blood. Biguanides also tend to make the cells of the body more willing to absorb glucose already present in the blood stream, and there again reducing the level of glucose in the plasma.
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Metformin
Structure
Systemic (IUPAC) Name N,N-dimethylimidodicarbonimidic diamide Chemical data FORMULA MOLECULAR MASS
C4H11N5
129.164 g/mol (free) 165.63 g/mol (HCl) 1,1-dimethylbiguanide
Pharmacokinetic data
SYNONYMS
Oral
It is used as an oral antihyperglycemic drug for the management of Type 2 diabetes mellitus. It is invariably recommended either as monotherapy or as an adjunct to diet or with a sulphonylurea (combination) to reduce blood-glucose levels.
Mechanism of Action
The drug is found to lower both basal and postprandial glucose. Interestingly, its mechanism of action is distinct from that of sulphonylureas and does not cause hypoglycemia. However, it distinctly lowers hepatic glucose production, reduces intestinal absorption of glucose, and ultimately improves insulin sensitivity by enhancing appreciably peripheral glucose uptake and its subsequent utilization. The drug is mostly eliminated unchanged in the urine, and fails to undergo hepatic metabolism.
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Synthesis of Metformin
Procedure Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is an oral antihyperglycemic drug used in the management of diabetes. It is usually prepared from the reaction between dimethylamine hydrochloride and dicyano diamide at 120-140 oC in 4 hrs time with 69% yield. In designing ecofriendly synthesis of the target molecule, the starting materials are made to react by modifying the reaction conditions in such a way that the by-products and wastes are eliminated and also the use of organic solvents is minimized.Thin layer chromatography (TLC) has been reported as a tool for reaction optimization in microwave assisted synthesis. This method has been used to modify a conventional procedure for an efficient synthesis of metformin hydrochloride by simply spotting of the reaction mixture on a TLC plate and then subjecting it to microwave irradiation.
Formulations
Metformin is sold under several trade names, including Glucophage XR, Riomet, Fortamet, Glumetza, Obimet, Dianben, Diabex, and Diaformin. Metformin IR (immediate release) is available in 500 mg, 850 mg, and 1000 mg tablets, all now generic in the US.
Buformin
Structure
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Chemical data FORMULA MOLECULAR MASS Pharmacokinetic data EXECRETION ROUTES LEGAL STATUS
C6H15N5
157.217 g/mol
Renal Oral
Withdrawn in most countries
Buformin is an anti-diabetic drug of the biguanide class, it is chemically related to metformin, and phenformin. It was withdrawn from the market in most countries due to a high risk of causing lactic acidosis. This drug is still used in some countries, such as Romania and Spain. It is marketed by German pharmaceutical company Grnenthal.
Phenformin
Structure
C10H15N5
205.26 g/mol
Phenformin is an anti-diabetic drug from the biguanide class. It was marketed as DBI by Ciba-Geigy but was withdrawn from most markets in the late 1970s due to a high risk of lactic acidosis, which was fatal in 50% of cases.
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6.2 Thiazolidinedione
The medication class of thiazolidinedione (also called glitazones) was introduced in the late 1990s as an adjunctive therapy for diabetes mellitus (type 2) and related diseases.
Insulin resistance is decreased Adipocyte differentiation is modified VEGF-induced angiogenesis is inhibited Leptin levels decrease (leading to an increased appetite) Levels of certain interleukins (e.g. IL-6) fall Adiponectin levels rise
6.2.2 Synthesis of N-substituted 2, 4-thiazolidinediones from oxazolidinethiones A novel reaction has been found between oxazolidinethione and bromoacetyl bromide to afford N-substituted 2,4-thiazolidinediones through an intramolecular nucleophilic substitution reaction. Interestingly a step of elimination was carried out in trisubstituted oxazolidinethiones forming a double bond.
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Chemically, the members of this class are derivatives of the parent compound thiazolidinedione, and include:
Rosiglitazone (Avandia) Pioglitazone (Actos) Troglitazone (Rezulin), which was withdrawn from the market due to an increased incidence of drug-induced hepatitis.
6.2.4 Uses
The only approved use of the thiazolidinediones is in diabetes mellitus type 2. It is being investigated experimentally in polycystic ovary syndrome (PCOS), nonalcoholic steatohepatitis (NASH), psoriasis, autism, and other conditions. Several forms of lipodystrophy cause insulin resistance, which has responded favorably to thiazolidinediones. There are some indications that thiazolidinediones provide some degree of the protection against initial stages of the breast carcinoma development.
Pioglitazone
STRUCTURE
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Chemical data FORMULA MOLECULAR MASS Pharmacokinetic data PROTEIN BINDING METABOLISM HALF LIFE EXECRETION ROUTES
C19H20N2O3S
356.44 g/mol
>99 %
liver (CYP2C8) 37 hours In bile
Oral
Pioglitazone is a prescription drug of the class thiazolidinedione (TZD) with hypoglycemic (antihyperglycemic, antidiabetic) action. Pioglitazone is marketed as trademarks Actos in the USA and UK, Glustin in Europe, Zactos in Mexico by Takeda Pharmaceuticals & Piozer in Pakistan by Hilton Pharmaceuticals. Actos was the tenth-best selling drug in the U.S. in 2008, with sales exceeding $2.4 billion. Side effects Pioglitazone can cause fluid retention and peripheral edema. As a result, it may precipitate congestive heart failure (which worsens with fluid overload in those at risk). It may cause anemia. Mild weight gain is common due to increase in subcutaneous adipose tissue. In studies, patients on pioglitazone had a slightly increased proportion of upper respiratory tract infection, sinusitis, headache, myalgia and tooth problems.
Rivoglitazone
Structure
Systemic (IUPAC) Name (RS)-5-{4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy]benzyl}-1,3-thiazolidine-2,4-dione Chemical data FORMULA MOLECULAR MASS
C20H19N3O4S
397.448 g/mol
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Rivoglitazone (INN) is a thiazolidinedione undergoing research for use in the treatment of type 2 diabetes. It is being developed by Daiichi Sankyo Co.
Rosiglitazone
STRUCTURE
Systemic (IUPAC) Name (RS)-5-[4-(2-[methyl(pyridin-2-yl)amino]ethoxy)benzyl]thiazolidine-2,4-dione Chemical data FORMULA MOLECULAR MASS Pharmacokinetic data BIOAVAIBILITY PROTEIN BINDING METABOLISM HALF LIFE EXECRETION ROUTES
C18H19N3O3S
357.428 g/mol
99 % 99.8 %
Hepatic (CYP2C8-mediated)
3 4 hours
Renal (64%) and fecal (23%)
Oral
Rosiglitazone is an anti-diabetic drug in the thiazolidinedione class of drugs. It is marketed by the pharmaceutical company GlaxoSmithKline as a stand-alone drug (Avandia) and in combination with metformin (Avandamet) or with glimepiride (Avandaryl). Annual sales peaked at approx $2.5bn in 2006. The drug's patent expires in 2012. Some reports have suggested that rosiglitazone is associated with a statistically significant risk of heart attacks, but other reports have disagreed, and the controversy has not been resolved. Concern about adverse effects has reduced the use of rosiglitazone despite its important and sustained effects on glycemic control.
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Troglitazone
Structure
Systemic (IUPAC) Name 5-(4-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy]benzyl)thiazolidine-2,4-dione Chemical data FORMULA MOLECULAR MASS HALF LIFE
C24H27NO5S
441.541 g/mol 16-34 hours
Troglitazone
(Rezulin,
Resulin
or
Romozin)
is
an
anti-diabetic
and
antiinflammatory drug, and a member of the drug class of the thiazolidinediones. It was developed by Daiichi Sankyo Co.(Japan). It was introduced and manufactured by ParkeDavis in the late 1990s but turned out to be associated with an idiosyncratic reaction leading to drug-induced hepatitis. Evaluating FDA medical officer Dr. John Gueriguian had disapproved it due to high liver toxicity. But the FDA stripped Gueriguian of his post and discarded his report under successful corporate pressure to approve the drug. It was withdrawn from the United Kingdom market (sailing by Glaxo) on December 1997.after,from the USA market on 21 March 2000, and from the Japan markets(introduced and manufactured by Sankyo.Co.) soon afterwards.
Mode of action
Troglitazone, like the other thiazolidinediones (pioglitazone and rosiglitazone), works by activating PPARs (peroxisome proliferator-activated receptors). Troglitazone is
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a ligand to both PPAR and - more strongly - PPAR. Troglitazone also contains an tocopheroyl moiety, potentially giving it vitamin E-like activity in addition to its PPAR activation. It has been shown to reduce inflammation: troglitazone use was associated with a decrease of nuclear factor kappa-B (NFB) and a concomitant increase in its inhibitor (IB). NFB is an important cellular transcription regulator for the immune response.
ANTI-DIABETIC AGENTS
agonists Tesaglitazar (AZ-242) by Astra Zeneca, reportedly in phase III clinical trial, Ragaglitazar (DRF-2725) by Dr. Reddys Research foundation, reportedly completed phase clinical trial but clinical development being terminated due to an incidence of bladder tumors in rodents. LY-510925 is a result of collaborative effort of Ellily Lilly and Ligand pharmaceuticals, Muraglitazar (BMS 298585) is disclosed by Cheng et al.
Aleglitazar
Structure
C24H23NO5S
437.50812 gm/mol
Aleglitazar is a peroxisome proliferator-activated receptor agonist (hence a PPAR modulator ) with affinity to PPAR and PPAR, which is being developed by Hoffmann La Roche for the treatment of type II diabetes. It is currently in phase II clinical trials.
Muraglitazar
Structure
C29H28N2O7
516.54 g/mol
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Muraglitazar (proposed tradename Pargluva) is a peroxisome proliferator-activated receptor agonist with affinity to PPAR and PPAR. The drug had completed phase III clinical trials, however in May, 2006 BristolMyers Squibb announced that it had discontinued further development.
Tesaglitazar
Structure
Systemic (IUPAC) Name (2S)-2-Ethoxy-3-[4-[2-(4-methylsulfonyloxyphenyl)ethoxy]phenyl]propanoic acid Chemical data FORMULA MOLECULAR MASS
C20H24O7S
408.46 gm/mol
Tesaglitazar is a peroxisome proliferator-activated receptor agonist with affinity to PPAR and PPAR, proposed for type 2 diabetes. The drug had completed several phase III clinical trials, however in May, 2006 AstraZeneca announced that it had discontinued further development.
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7.5 Carcinogenicity
All insulin analogs must be tested for carcinogenicity, as insulin engages in crosstalk with IGF pathways, which can cause abnormal cell growth and tumorigenesis. Modifications to insulin always carry the risk of unintentionally enhancing IGF signalling in addition to the desired pharmacological properties.
Insulin aspart
Chemical data FORMULA MOLECULAR MASS ROUTES
C256H381N65O79S6
5825.8 g/mol Subcutaneous
Insulin aspart (marketed by Novo Nordisk as "NovoLog/NovoRapid") is a fast acting insulin analogue. It was created through recombinant DNA technology so that the amino acid, B28, which is normally proline, is substituted with an aspartic acid residue. This analogue has increased charge repulsion, which prevents the formation of hexamers, to create a faster acting insulin. The sequence was inserted into the yeast genome, and the yeast expressed the insulin analogue, which was then harvested from a bioreactor. The components of insulin aspart are as follows: Metal ion zinc (19.6 ug/mL) Buffer disodium hydrogen phosphate dihydrate (1.25 mg/mL) Preservative m-cresol (1.72 mg/mL) and phenol (1.50 mg/mL) Isotonicity agent glycerin (16 mg/mL) and sodium chloride (0.58 mg/mL). The pH of insulin aspart is 7.2-7.6. According to JDRF, insulin aspart was approved for marketing in the United States by the Food and Drug Administration in June 2000.
Insulin glargine
Systemic (IUPAC) Name Recombinant human insulin Chemical data FORMULA MOLECULAR MASS ROUTES
C267H408N72O77S6
6063 g/mol Subcutaneous
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Insulin glargine, marketed by Sanofi-Aventis under the name Lantus, is a longacting basal insulin analogue, given once daily to help control the blood sugar level of those with diabetes. Its advantage is that it has a duration of action of 24 hours, with a "less peaked" profile than NPH. Thus, it more closely resembles the basal insulin secretion of the normal pancreatic beta cells. Sometimes, in type 2 diabetes and in combination with a short acting sulfonylurea (drugs which stimulate the pancreas to make more insulin), it can offer moderate control of serum glucose levels. In the absence of endogenous insulinType 1 diabetes, depleted type two (in some cases) or latent autoimmune diabetes of adults in late stageLantus needs the support of fast acting insulin taken with food to reduce the effect of prandially derived glucose. It is fasting glucose elevation which more significantly affects HbA1c and thus determines the progression of the long-term complications of diabetes mellitus.
Insulin detemir
Structure
Chemical data FORMULA MOLECULAR MASS Pharmacokinetic data BIOAVAIBILITY HALF LIFE ROUTES
C267H402N64O76S6
5913 gm/mol 60% (when administered s.c.)
5-7 hours
Subcutaneous
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Insulin detemir is a long-acting human insulin analogue for maintaining the basal level of insulin. Novo Nordisk markets it under the trade name Levemir. It is an insulin analogue in which a fatty acid (myristic acid) is bound to the lysine amino acid at position B29 . It is quickly resorbed after which it binds to albumin in the blood through the fat acid at position B29. It then slowly dissociates from this complex. Insulin lispro
Chemical data FORMULA MOLECULAR MASS
C257H389N65O77S6
5813.63 g/mol
Insulin lispro (marketed by Eli Lilly and Company as "Humalog") is a fast acting insulin analogue; it was the first insulin analogue.
Insulin glulisine
Chemical data FORMULA MOLECULAR MASS ROUTES
C258H384N64O78S6
5823 gm/mol Subcutaneous
Insulin glulisine is a rapid-acting insulin analogue that differs from human insulin in that the amino acid asparagine at position B3 is replaced by lysine and the lysine in position B29 is replaced by glutamic acid. Chemically, it is 3B-lysine-29B-glutamic acidhuman insulin, has the empirical formula C258H384N64O78S6 and a molecular weight of 5823. It was developed by Sanofi-Aventis and sold under the trade name Apidra. When injected subcutaneously, it appears in the blood earlier and at higher concentrations than human insulin. When used as a meal time insulin, the dose should be given within 15 minutes before a meal or within 20 minutes after starting a meal.
NPH insulin
NPH insulin; also known as Humulin N, Novolin N,Novolin NPH, NPH Lletin II, and isophane insulin, marketed by Eli Lilly and Company under the name Humulin N, is an intermediate-acting insulin given to help control the blood sugar level of those with
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diabetes. NPH stands for Neutral Protamine Hagedorn and was created in 1936 when Nordisk formulated "isophane" porcine insulin by adding Neutral Protamine to regular insulin. It was dubbed Neutral Protamine Hagedorn or NPH. This is a suspension of crystalline zinc insulin combined with the positively charged polypeptide, protamine. When injected subcutaneously, it has an intermediate duration of action, meaning longer than that of regular insulin, but shorter than ultralente, glargine or detemir.
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8. Other analogs
8.1 -Glucosidase inhibitor
-Glucosidase inhibitors are oral anti-diabetic drugs used for diabetes mellitus type 2 that work by preventing the digestion of carbohydrates (such as starch and table sugar). Carbohydrates are normally converted into simple sugars (monosaccharides), which can be absorbed through the intestine. Hence, alpha-glucosidase inhibitors reduce the impact of carbohydrates on blood sugar. 8.1.1 Examples and differences Examples of alpha-glucosidase inhibitors include:
Even though the drugs have a similar mechanism of action, there are subtle differences between acarbose and miglitol. Acarbose is an oligosaccharide, whereas miglitol resembles a monosaccharide. Miglitol is fairly well-absorbed by the body, as opposed to acarbose. Moreover, acarbose inhibits pancreatic alpha-amylase in addition to alpha-glucosidase. 8.1.2 Natural glucosidase inhibitors Research has shown the culinary mushroom Maitake (Grifola frondosa) has a hypoglycemic effect. The reason Maitake lowers blood sugar is due to the fact the mushroom naturally contains a alpha glucosidase inhibitor. 8.1.3 Mechanism of action Alpha-glucosidase inhibitors are competitive, reversible inhibitors of pancreatic amylase and membrane-bound intestinal -glucosidase hydrolase enzymes. Acarbose, the first -glucosidase inhibitor discovered, is a nitrogen-containing pseudotetrasaccharide, while miglitol is a synthetic analog of 1-deoxynojirimycin. The mechanism of action of these inhibitors is similar but not identical. They bind competitively to the oligosaccharide binding site of the -glucosidase enzymes, thereby preventing enzymatic hydrolysis. Acarbose binding affinity for the -glucosidase enzymes is: glycoamylase > sucrase >
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maltase > dextranase. Acarbose has little affinity for isomaltase and no affinity for the glucosidase enzymes, such as lactase. Miglitol is a more potent inhibitor of sucrase and maltase that acarbose, has no effect on -amylase, but does inhibit intestinal isomaltose. The major side effects of the -glucosidase inhibitors are related to gastrointestinal disturbances. These occur in approximately 25-30% of diabetic patients, and include flatulence, diarrhea, bloating, and abdominal discomfort. Daily dose of acabose and miglitol is 25-100mg. 8.1.4 SAR of -Glucosidase inhibitors An extensive search for -Glucosidase inhibitors from microbial cultures led to the isolation of acarbose from an actinomycete. Extensive structure activity investigations revealed that active -glucosidase inhibitors have a common pharmacophore, comprising a substituted cyclohexane ring and a 4,6-dideoxy-4-amino-D-glucose unit known as carvosine. It appears that the secondary amino group of this core structure prevents an essensial carboxyl group of the -glucosidase from protonating the glycosidic oxygen bonds of the substrate. Most recently, screening programs of small molecules have yielded several other -glucosidase inhibitors resembling simple amino sugar as miglitol and voglibose.
Acarbose
Structure
Systemic (IUPAC) Name (2R,3R,4R,5S,6R)-5-{[(2R,3R,4R,5S,6R)-5- {[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl- 5{[(1S,4R,5S,6S)-4,5,6-trihydroxy-3- (hydroxymethyl)cyclohex-2-en-1-yl]amino} tetrahydro-2H-pyran-2yl]oxy}-3,4-dihydroxy- 6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}- 6-(hydroxymethyl)tetrahydro2H-pyran-2,3,4-triol
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Chemical data FORMULA MOLECULAR MASS
C25H43NO18
645.605 g/mol
Pharmacokinetic data
It is used in the control and management of Type 2 diabetes mellitus. Mechanism of Action The drug, which is obtained from the microorganism Actinoplane utahensis, is found to a complex oligosaccharide that specifically delays digestion of indigested carbohydrates, thereby causing in a smaller rise in blood glucose levels soonafter meals. It fails to increase insulin secretion; and its antihyperglycemic action is usually mediated by a sort of competitive, reversible inhibition of pancreatic -amylase membrane-bound intestinal -glucosidase hydrolase enzymes. The drug is metabolized solely within the GI tract, chiefly by intestinal bacteria but also by diagestive enzymes.
Miglitol
Structure
Systemic (IUPAC) Name (2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol Chemical data FORMULA MOLECULAR MASS Pharmacokinetic data BIOAVAIBILITY
C8H17NO5
207.224 g/mol Dose-dependent
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PROTEIN BINDING HALF LIFE EXECRETION ROUTES
Negligible (<4.0%)
2 hours
Renal (95%)
Oral
Mechanism of Action
It resembles closely to a sugar, having the heterocyclic nitrogen serving as an isosteric replacement of the sugar oxygen. The critical alteration in its structure enables its recognition by the -glycosidase as a substrate. The ultimate outcome is the overall competitive inhibition of the enzyme which eventually delays complex carbohydrate absorption from the ensuing GI tract.
Voglibose
Structure
C10H21NO7
267.28 g/mol
Voglibose (trade name Voglib, marketed by Mascot Health Series) is an alphaglucosidase inhibitor used for lowering post-prandial blood glucose levels in people with diabetes mellitus. Postprandial hyperglycemia (PPHG) is primarily due to first phase insulin secretion. Alpha glucosidase inhibitors delay glucose absorption at the intestine level and thereby prevent sudden surge of glucose after a meal. There are three drugs which belong to this class, acarbose, miglitol and voglibose, of which voglibose is the newest. Voglibose scores over both acarbose and miglitol in terms of side effect profile.
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8.2 Amylin
8.2.1 Islet amyloid polypeptide
Figure No. 8.1 Amino acid sequence of amylin with disulfide bridge and cleavage sites of insulin degrading enzyme indicated with arrows
Amylin, or Islet Amyloid Polypeptide (IAPP), is a 37-residue peptide hormone secreted by pancreatic -cells at the same time as insulin (in a roughly 1:100 amylin:insulin ratio). 8.2.2 Pharmacology Synthetic amylin, or pramlintide (brand name Symlin), was recently approved for adult use in patients with both diabetes mellitus type 1 and diabetes mellitus type 2. Insulin and pramlintide, injected separately but both before a meal, work together to control the post-prandial glucose excursion. Amylin is degraded in part by insulin-degrading enzyme. 8.2.3 Receptors There appears to be at least three distinct receptor complexes that bind with high affinity to amylin. All three complexes contain the calcitonin receptor at the core, plus one of three receptor activity-modifying proteins, RAMP1, RAMP2, or RAMP3.
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Pramlintide
Structure
Chemical data FORMULA MOLECULAR MASS Pharmacokinetic data BIOAVAIBILITY PROTEIN BINDING METABOLISM HALF LIFE ROUTES
C171H269N51O53S2
3951.41 g/mol
30-40%
Approximately 60%
Renal
Approximately 48 minutes Subcutaneous
Pramlintide acetate (Symlin) is a relatively new adjunct treatment for diabetes (both type 1 and 2), developed by Amylin Pharmaceuticals. Side effects The major side effects reported for pramlintide consist of mild to moderate nausea, with sever nausea appearing in patients using large doses of the drug. The nausea may decrease on continued use of the drug. The rate of hypoglysemia appears to be quite low.
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Dapagliflozin
Structure
Systemic (IUPAC) Name (2S,3R,4R,5S,6R)-2-[4-chloro-3(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol Chemical data FORMULA MOLECULAR MASS SYNONYMS
C21H25ClO6
408.873 g/mol (1S)-1,5-anhydro-1-C-{4-chloro-3- [(4ethoxyphenyl)methyl]phenyl}-D-glucitol
ROUTES
Oral
Dapagliflozin is an experimental drug being studied by Bristol-Myers Squibb in partnership with AstraZeneca as a potential treatment for type 1 and 2 diabetes. Although dapagliflozin's method of action would operate on either type of diabetes or other conditions resulting in hyperglycemia, the current clinical trials specifically exclude participants with Type 1 diabetes.
Method of action
Dapagliflozin inhibits subtype 2 of the sodium-glucose transport proteins (SGLT2), which is responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter causes blood glucose to be eliminated through the urine.
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Remogliflozin etabonate
Systemic (IUPAC) Name 5-methyl-4-[4-(1-methylethoxy)benzyl]-1-(1-methylethyl)-1H-pyrazol-3-yl 6-O-(ethoxycarbonyl)--Dglucopyranoside Chemical data FORMULA MOLECULAR MASS ROUTES
C26H38N2O9
522.586 g/mol
Oral
Remogliflozin etabonate is a proposed drug for the treatment of type 2 diabetes being investigated by GlaxoSmithKline.
Method of action
Remogliflozin inhibits the sodium-glucose transport proteins, which are responsible for glucose reabsorption in the kidney. Blocking this transporter causes blood glucose to be eliminated through the urine.
Sergliflozin etabonate
Systemic (IUPAC) Name 2-(4-methoxybenzyl)phenyl 6-O-(ethoxycarbonyl)--D-glucopyranoside Chemical data FORMULA MOLECULAR MASS ROUTES
C23H28O9
448.463 g/mol
Oral
Method of action
Sergliflozin inhibits subtype 2 of the sodium-glucose transport proteins (SGLT2), which is responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter causes blood glucose to be eliminated through the urine.
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9. Other Drugs
Tolrestat
Structure
C16H14F3NO3S
357.34 g/mol
Tolrestat is an aldose reductase inhibitor which was approved for the control of certain diabetic complications. It was discontinued by Wyeth in 1997 because of the risk of severe liver toxicity and death. It was sold under the tradename Alredase.
Synthesis of Tolrestat
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Benfluorex
Systemic (IUPAC) Name (RS)-2-({1-[3-(trifluoromethyl)phenyl]propan- 2-yl}amino)ethyl benzoate Chemical data FORMULA MOLECULAR MASS EXECRETION ROUTES
C19H20F3NO2
351.363 g/mol
Renal Oral
Benfluorex is an anorectic and hypolipidemic agent. Clinical studies have shown it may improve glycemic control and decrease insulin resistance in people with poorly controlled type 2 diabetes. It is marketed in France as an adjuvant antidiabetic. On 18 December 2009 the European Medicines Agency (EMEA) has recommended the withdrawal of all medicines containing benfluorex in the European Union, because their risks, particularly the risk of heart valve disease (fenfluramine-like cardiovascular side-effects), are greater than their benefits. Benfluorex is structurally related to fenfluramine.
Synthesis of Benfluorex
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a hypoglycemic effect, and may be beneficial for the management of diabetes. The reason Maitake lowers blood sugar is due to the fact the mushroom naturally acts as an alpha glucosidase inhibitor.Other mushrooms like Reishi, Agaricus blazei, Agrocybe cylindracea and Cordyceps have been noted to lower blood sugar levels to a certain extent, although the mechanism is currently unknown.
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11. References
1. Zimmet, P.Z.; Alberti, K. G. M. M.; Shaw, J., Nature 2001, 414, 782-787. 2. Rotella, D. P., J. Med. Chem. 2004, 47, 4111-4112. 3. Gerich J. E., Mayo Cli. Proc. 2003, 78, 447-456. 4. Kahn, S. E., Diabetologia 2003, 46, 3-19. 5. Goodman and Gilmans, The Pharmacological Basis of Therapeutics, 10th Ed., McGraw-Hill publication, 1996, pp.1686-1687. 6. National Diabetes Data Group: Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance, Diabetes 1972, 2, 1120. 7. Stride A.; Hattersley, A. T., Ann Med 2002, 34, 207-16. 8. Tattersall, R. B. and Pyke, D. A., Lancet 1972, 2, 1120. 9. Ross and Wilson, Anatomy and Physiology in health and illness, Kathleen, J. W.; Wilson OBE, Anne Waugh, 8th edition, Churchill livingstone publication, 1996, pp.233-240. 10. Burgers Medicinal Chemistry & Drug Discovery, 6th Edition, Vol 4: Autacoids, Diagnostic & Drugs from New Biology, John Willy & Sons, 2003, p.1-2. 11. Rang, H. D.; Dale, M. M.; Riter, J. M., Pharmacology, 3rd edition, Churchill livingstone publication, 1995, p.404-416. 12. Laurence, D. R.; Bennett, P. N.; Brown, M. J. Clinical pharmacology, 8th edition, Churchill livingstone publication, 1997, p.619-632. 13. Cheng, A.; Dube, N.; Gu, F.; Tremblay M. L., Eur. J. Biochem. 2002, 269, 10501059. 14. Atkinson, M. A.; Eisenbarth, G.S., Lancet 2001, 358, 221-229. 15. Kahn, S. E., Diabetologia 2003, 46, 3-19. 16. Douglas, E.; Bennie, M.; McAnaw, J., Pharm J 2001; 261: 810-18. 17. Pirart, J., Diabetes Care 1978, 1, 168.
Page 107
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18. Burg, M. B.; Kador, P. F., J. Clin. Inves.1988, 81, 635. 19. Frank, R. N., Diabetes 1994, 43, 169. 20. Raymond, A. A., Malaysian Journal of Medical Sciences 2003, 10, 27-30. 21. Banting, F.G.; Best, C.H., J. Lab. Clin. Med. 1922, 7, 256. 22. Abel, J., Proc. Nal. Acad. Sci. USA 1926, 12, 132. 23. Guiris, F.K.; Ghanem, M.H.; Abdel-hey, M.M., Arzeim - forsch. 1976, 26, 453. 24. Ducan, L.P. J; Baird, J.D., Pharmacol. Rev. 1960, 12, 91. 25. Hack, E., Arzeim - forsch. 1958, 8, 444. 26. Rusching, H.; Korger, G.; Aumuller, W.; Wagner, H.; Weyer, R; Bander, R.; Scholz, J., Arzeim- forsch. 1958, 8, 448. 27. Dvornik, D., Ann. Rep. Med. Chem. 1978, 13, 159. 28. Marble, A., Diabetes, 1967, 16, 825. 29. Aumullr, W.; Bander, A; Heerdt, R.; Muth, K.; Pfaff, W.; Schmidt, F.H.; Weber, H.; Weyer, R., Arzeim. Forsch. 1969, 16, 1346 30. Clark, D.A.; Goldstein, S.W.; Volkman, R.A.; Eggler, J.F.; Holland, G.F.; Hulin, B.; Stevenson, R.W.; Kreutter, D.K.; Gibbs, E.M.; Krupp, M.N.; Merigan, P.; Kelbaugh, P.L.; Andrews, E.G.; Tickner, D.L.; Suleske, R.T.; lamphere, C.H.; Rajekas, F.J.; Kappeler, W.H.; Mcdermott, R.E.; Hutson, N.J.; Johnson, M.R., J. Med. Chem. 1991, 34, 319-325. 31. Mamose, Yu.; Shohda, T.; Meguro, Kanji., Chem. Pharm. Bull. 1991, 39, 1440. 32. Katsutoshi, M.; Mamose, Yu.; Shohda, T.; Meguro, K.; Ikeda, H., J. Med. Chem. 1992, 35, 2617-2626. 33. Cantello, B, C.C.; Cawthorne, M.A.; Cottam, G.P.; Duff, P.T.; Haigh, D.; Hindley, R.M.; Lister, C.A.; Smith, S.A.; Thurlby, P.L., J. Med. Chem. 1994, 37, 39773985. 34. Lohray, B.B.; Bhusan, V.; Rao, P.B.; Madhvan, G.R.; Murali, N.; Rao. K.N.; Reddy, A.K.; Rajesh, B.M.; Reddy, P.G.; Chakrabarty, R.; Vikramadityan, R.K.;
Page 108
ANTI-DIABETIC AGENTS
Rajagopalan, R.; MamidiRao, N.V.S.; Jajoo, H.K. ; Subramaniam, S., J. Med. Chem. 1998, 41, 1619-1630. 35. Lohray, B.B.; Bhusan, V.; Reddy, A.S.; Rao, P.B.; Reddy, N.J.; Harikishore, P.; Haritha, N.; Vikramadityan, R.K.; Chakrabarty, R.; Rajagopalan, R.; Katneni, K., J. Med. Chem. 1999, 42, 2569-2581. 36. Nomura, M.; Kinosita, S.; Satoh, H.; Maeda, T.; Murakami, K.; Tsunoda, Miyachi, H.; Awano, K., Bior. Med. Chem. Lett. 1999, 9, 533-538 37. Oguchi, M.; Wada, K.; Honma, H.; Tanaka, A.; Kaneko, T.; Sakakibara, S.; Ohsumu, J.; Serizava, N.; Fugiwara, T.; Horikoshi, H.; Fugita, T., J. Med. Chem. 2000, 42, 2569-2581. 38. Desai, R.C.; Wei, H.; Metzger, E.J.; Bergman, J.P.; Gratale, D.F.; Macnaul, K.L.; Berger, J.P.; Doebber, T.W.; Kwan, L.; Moller, D.E.; Heck, J.V.; Sahoo, S.P., Bior. Med. Chem. Lett. 2003, 13, 2795-2798. 39. Bhatt, A.B.; Ponnala, S.; Sahu, D.P.; Tiwari, P.; Tripathi, B.K.; Srivastava, A. K., Bior. Med. Chem. 2004, 12, 5857-5864. 40. Willson, T. M.; brown, P. J.; Srenbach, D. D., J. Med. Chem. 2000, 43, 527-550. 41. Liao, C.; Xie, A.; Shi, L.; Z., Jiaju; L., X., J. Chem. Inf. Comput. Sci. 2004, 44, 230-238. 42. Wahli, W.; Braissant, O.; Desvergne, B., Chem. Biol. 1995, 5, 571-576. 43. Nolte, R. T.; Wisely, G. B.; Westin, S.; Cobb, J. E.; Lambert, M. H.; Kurokawa, R.; Rosenfeld, M. G.; Willson, T. M.; Glass, C. K.; Milburn, M. V., Nature 1998, 395, 137-43. 44. Laudet V, Hanni C, Coll J, Embo J. 1992, 11, 1003-1013. 45. Xu, H. E.; Lambert, M. H.; Montana, V. G. ; Parks, D. J.; Blanchard, S. G.; Brown, P. J.; Sternbach, D. D.; Lehmann, J. M.; Wisely, G. B.; Willson, T. M.; Kliewer, S. A.; Milburn, M. V., Mol Cell 1999, 3, 397-403. M.;
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