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Antihyperlipidemics 1& 2 Pharm 732 2014

Required reading: Foye, Principles of Medicinal Chemistry,

Learning Objectives 1) Know the classes of antihyperlipidemic agents and recognize systematic name, structure 2) Understand their mechanism of action, and how their structure drives this 3) Know how structure drives their ADMET 4) Be able to describe rational combinations of therapy based upon MOA Specific learning objectives 1. Delineate the complementary natures of cholesterol lowering drugs. How can mechanisms synergize. How are the drugs structures related to their activity 2. Describe differing modes of action of lipid modifying drugs, and how activities and side effects are tied to structure.

Antihyperlipidemics 1& 2 Pharm 731.

There is a huge body of evidence showing atherosclerosis progression & cardiac event death can be modified by altering blood lipoproteins:

Relation of Serum Cholesterol Levels to the AgeAdjusted Rate of Death from Ischemic Heart Disease during an Average Follow-up Period of Six Years among 361,662 Men Screened for the MRFIT Study.

LaRosa JC, Hunninghake D, Bush D, et al. Circulation 1990; 81:1721-1733

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Antihyperlipidemics 1& 2 Pharm 731 Think-----Why do we have lipoproteins? Initially thought just reducing cholesterol important, as lots of cholesterol found in atherosclerotic plaques examined post-mortem. Brought about drug development programs to reduce cholesterol. Cholesterol reduction had beneficial effects. Cholesterol is both synthesized by the body (primarily in liver) and obtained from diet. Later found that ratio between LDL and HDL also very important Decrease LDL & Increase HDL = Lowered Atherosclerosis Drugs acting either to decrease total cholesterol, or to alter HDL to LDL ratios have beneficial effects. In the case of decreasing cholesterol there are a number of possible mechanisms to use.

Cholesterol- Diet & Synthesized

Lets rule of 5 absorbed cholesterol Mw 386 OK? H donors = H acceptors = 1 - OK? LogP 7.5 - OK?

Predict bioavailability of cholesterol

A High B Intermediate C Low unless transporter D Low unless food effects (fatty meal)

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Cholesterol- Diet & Synthesized

Lets rule of 5 absorbed cholesterol Mw 386 OK? H donors = H acceptors = 1 - OK? LogP 7.5 - OK?

Predict bioavailability of cholesterol

A High B Intermediate C Low unless transporter D Low unless food effects (fatty meal)

1) Inhibiting Cholesterol Absorption from Diet- a) Plant Sterols compete with cholesterol A range of cholesterol-like sterols found in plants compete for cholesterol absorption sites in the GI tract

Not metabolized to form cholesterol. Now some margarines contain up to 20% sterols, have a significant effect on total and LDL cholesterol (~10 and 14% reductions) Cholest-off & similar capsules of plant sterols. Reduction of Serum Cholesterol with Sitostanol-Ester Margarine in a Mildly Hypercholesterolemic Population Tatu A. Miettinen, M.D., Pekka Puska, M.D., Helena Gylling, M.D., Hannu Vanhanen, M.D., and Erkki Vartiainen, M.D. NEJM 333:1308-1312 )1995) Conclusions Substituting sitostanol-ester margarine for part of the daily fat intake in subjects with mild hypercholesterolemia was effective in lowering serum total cholesterol and LDL cholesterol

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1) Inhibiting Cholesterol Absorption from Diet- a) Plant Sterols compete with cholesterol Rarely side effects 17-year-old girl presented with: multiple xanthomas of the hands & familal CV disease. Familial hypercholesterolemia suspected, but theplasma cholesterol level was only mildly elevated. Plasma levels of plant sterols (GC) 950 mol of sitosterol per liter (normal value, <16) and 378 mol of campesterol per liter (norma l value, <24). Phytosterolemia is an autosomal recessive disorder with increased intestinal absorption of dietary sterols (not only cholesterol, but also plant sterols) and decreased biliary excretion of sterols. Consequently, large amounts of plant sterols accumulate in most tissues, and xanthomas and premature cardiovascular disease develop. Mutations in the genes encoding the family of ATP-binding cassette transporters(ABCG5 andABCG8), which pump sterols out of intestinal cells in the lumen of the gut, have recently been shown to be involved in causing phytosterolemia. The patient was told to follow a diet low in plant fats (margarines), nuts, chocolate, and seeds. In addition, bile acid resins were prescribed. 5 years low plant sterol diet (Panel B). n engl j med 349;1 www.nejm.org july3, 2003

1) Inhibiting Cholesterol Absorption from Diet- b) Ezetimibe Zetia, & Vytorin A New class of compounds. Selectively inhibits cholesterol uptake by acting upon intestine

How was ezetimibe developed?

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Schering Plough team looking at inhibitors of Acyl-CoA-Cholesterol Acyl Transferase (ACAT): plays key roles in cholesterol absorption, storage and transport.

Schering Plough team looking at inhibitors of Acyl-CoA-Cholesterol Acyl Transferase (ACAT): Cyclic amide (beta lactam) had better activity, esp in an in vivo screen (chol fed hamster)

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Did a big synthesis of analogs to define SAR . Poor ACAT IC50 led to belief that non-ACAT mechanisms involved.

Studying metabolism identified sites for improvement.

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High activity, and Stereospecificity Led to Hypothesis that a protein is inhibited- a cholesterol transporter in gut? Screened cDNAs from rat jejunum, rationally picked proteins with: cell surface expression, sterol sensing domain etc. Made knockouts in mice from screen. led to Science, Vol 303, Issue 5661, 1201-1204 , 20 February 2004 Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption

Scott W. Altmann,1* Harry R. Davis, Jr.,1 Li-ji Zhu,1 Xiaorui Yao,1 Lizbeth M. Hoos,1 Glen Tetzloff,1 Sai Prasad N. Iyer,1 Maureen Maguire,2 Andrei Golovko,2 Ming Zeng,2 Luquan Wang,2 Nicholas Murgolo,2 Michael P. Graziano1

Science, Vol 303, Issue 5661, 1201-1204 , 20 February 2004

Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption

Scott W. Altmann,1* Harry R. Davis, Jr.,1 Li-ji Zhu,1 Xiaorui Yao,1 Lizbeth M. Hoos,1 Glen Tetzloff,1 Sai Prasad N. Iyer,1 Maureen Maguire,2 Andrei Golovko,2 Ming Zeng,2 Luquan Wang,2 Nicholas Murgolo,2 Michael P. Graziano1

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Metabolism of Ezetimibe Simple metabolism. Glucuronide activity > parent phenol Uptaken, glucuronidated, hepatobiliary excretion of active glucuronide.

This is major active component

This explains some of SAR

Only need glucuronidation of ezetimibe, instead of sequential O-demethylation & glucuronidation, higher yield of active SCH 60663

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Coadministration with a statin beneficial in a dog model.

Low dose individually had no effects. Together very effective. Points to HMG CoA Reductase induction by Ezetimibe

Davis, H. R., Jr.; Pula, K. K.; Alton, K. B.; Burrier, R. E.; Watkins, R. W. The synergistic hypocholesterolemic activity of the potent cholesterol absorption inhibitor, ezetimibe, in combination with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in dogs. Metab., Clin. Exp. 2001, 50, 1234-1241.

Coadministration with a statin beneficial in trials.

Dujovne, C. A.; Ettinger, M. P.; McNeer, J. F.; Lipka, L. J.; LeBeaut, A. P.; Suresh, R.; Yang, B. O.; Veltri, E. P. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am. J. Cardiol. 2002, 90 (10), 1092-1097. [ChemPort] [Medline] [CrossRef] (b) Davidson, M. H.; McGarry, T.; Bettis, R.; Melani, L.; Lipka, L. J.; LeBeaut, A. P.; Suresh, R.; Sun, S.; Veltri, E. P. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J. Am. Coll. Cardiol. 2002, 40 (12), 2125-2134. [ChemPort] [Medline] [CrossRef] See also ref 5. (c) Gagne, C.; Bays, H. E.; Weiss, S. R.; Mata, P.; Quinto, K.; Melino, M.; Cho, M.; Musliner, T. A.; Gumbiner, B. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am. J. Cardiol. 2002, 90 (10), 1084-1091. [ChemPort] [Medline] [CrossRef] (d) Ballantyne, C. M.; Houri, J.; Notarbartolo, A.; Melani, L.; Lipka, L. J.; Suresh, R.; Sun, S.; LeBeaut, A. P.; Sager, P. T.; Veltri, E. P. Effect of Ezetimibe Coadministered with Atorvastatin in 628 Patients with Primary Hypercholesterolemia. Circulation 2003, 107 (19), 2409-2415.

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Combination of Ezetimibe & Statin marketedVYTORIN TM 10/10 to 10/80 Prevents both dietary absorption and hepatic synthesis Avoids dangers of stacking statins & fibrates.... lower statin doses.

2) Bile Acid Sequestrants In the liver, cholesterol is oxidized to form Bile Salts such as Cholic Acid: these are important in the emulsification of dietary fat, are secreted into the GI tract via the biliary system & recycled by uptake.

This carboxylic acid function gives name to the bile acids, and is important....

multiple oxidations

Much lower logP ~ 4

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Sequestrants are ion exchange resins, predominantly hydrophobic polymers with amine groups- tertiary or quaternary: Need to consume large amounts 10 to 30 g daily of a quite nasty powder Often GI problems constipation and gas. But very safe so used in young patients who will need therapy for a long time. Can bind some compounds (warfarin, vitamin K) & reduce absorption.

Bile salts bind strongly due to combination of ionic and hydrophobic interactions, -stomach or intestine? hence are NOT recycled but excreted in feces. This has the effect of increasing cholesterol metabolism (more bile salts must be made) and so slowly lowers blood cholesterol levels, as liver increases LDL receptors to get more cholesterol from blood.

Which of these compounds might also have lower bioavailability of given with BAS

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Which of these compounds might also have lower bioavailability of given with BAS

Overall Model.
Cholesterol absorption needs a transporter: Ezetimibe competitive inhibitor Sterols- competitive inhibitor Cholesterol metabolites are recirculated and can be scavenged. BAS- selective BA binder to promote fecal excretion

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3) Inhibitors of HMG-CoA Reductase. The enzyme HMG-CoA Reductase is the both the first and rate-limiting step of cholesterol biosynthesis. Thus inhibiting this enzyme will decrease cholesterol synthesis without causing the build-up of intermediates (cf Triparanol inhibits later enzymes, causes desmosterol accumulation- not used!) HMG is 3-hydroxy-3-methylglutaryl CoA This class of compounds are termed statins, all except fluvastatin are natural products from Penicillium or Aspergillus funghi.

Simvastatin 1st FDA approved, in 1991.

The similarity between all can be seen easily be seen, as can the similarity between the authentic HMG-CoA & also cholesterol hydrophobic groups (feedback inhibition) All except pravastatin& atorvastatin are prodrugs, with hydrolysis of the lactone by serum or tissue esterases needed.

Substrate inhibition
.

Direct reductase to proteolysis ?

Fluvistatin is synthetic, cheaper, still has HMG CoA and cholesterol-like groups

Statin kM nanomolar vs HMG CoA 4 uM

Fluvistatin does not require activation by esterases.

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Metabolism and Side Effects of statins Predominantly oxidative in phenyl rings by Cyp3A4. Most mono-oxidation products retain some activity. The most serious side effect of statins is Myopathy- breakdown of muscle cells releasing myoglobin. In large amounts this causes free radical damage to the kidneys- Rhabdomyolysis, as seen in crush injury. Alkalinization of urine slows reactions of ferryl-myoglobin, decreases cellular damage. (JBC 278 31731 1998) Especially in combination with Fibrates (see next). Baycol withdrawn but all can cause effect. Thought to be due to via inhibition of Cytochrome P450 3A4. Liver damage can also occur (needs care). Statins are generally extensively hepatically metabolized. Important Despite repeated FDA warnings that combining statins with fibrates causes Rhabdomyolysis, some physicians pursuing aggressive lipid lowering do combine. Baycol (cerivastatin) particularly susceptible, despite warning ~100 dead, withdrawn from market August 2001 Symptoms to be noted in counseling are: muscle pain & weakness, dark urine, fever malaise, nausea. Potential mechanism: Can in crease AUC for cerivastatin of ~ 500%, max plasma conc 300% (Gemfibrozil greatly increases plasma concentrations of cerivastatin Backman, JT ; Kyrklund, C ; Neuvonen, M ; Neuvonen, P Clinical Pharmacology & Therapeutics; DEC 2002; v.72, no.6, p.685-691)

Statins

Desmosterol accumulated as a result of triparanol

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4) Activation of Plasma Lipoprotein Lipase This enzyme is present in the endothelium and catalyzes the breakdown of lipoproteins so that their components can be taken up by peripheral cells. Thus activation of this enzyme increases lipoprotein breakdown rates, and decreases levels. Importantly, acts against high triglyceride levels, not just cholesterol This class of compounds with this action are called Fibrates All except Gemfibrozil and Ciprofibrate prodrugs that need activation by tissue esterases.

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Site of action of Fibrates is PPAR

Peroxisomal proliferator-activator receptor alpha

PPAR gamma is diabetes target interest in dual acting compounds

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Important features in SAR of Fibrates:

1) Phenyl group 2) Ether linkage between phenyl to a 2-methyl-2-carboxylic acid substituted alkyl chain. For all except Gemfibrozil this is a 2-methylpropanoic acid group, for gemfibrozil it is a 2,2-dimethylpentanoic acid group. 3) Generally, phenyl group substituted para (4-) to ether linkage with either chorine or a para-chlorophenyl-containing group. So, we want it to look like a fatty acid to PPAR, but not undergo beta-oxidation, esterification etc, Overall, less effective than statins. But useful, especially in hypertriglyceridemia (prevent pancreatitis). All are hydrophobic, usually highly protein bound, metabolized by formation of glucuronide at COO function (occasionally aromatic hydroxylation). Long lives allow for 1 or 2 daily doses.

5) Increased non-receptor/enzyme-based lipid clearance

The drug in this class is Probucol. Mechanism by which it acts is uncertain, probably ABCA1, inhibiting cell to lipoprotein lipid transfer. http://atvb.ahajournals.org/cgi/content/full/24/12/2345

Importantly obvious structural analogy to antioxidant BHT. Probucol strongly antioxidant, thought important in inhibiting lipid peroxidation in plaque formation. Such antioxidants form a stable, resonance-stabilized phenoxyl radical that inhibits free radical damage.

However, probucol as well as lowering LDL, also lowers HDL, QT extender so not currently available in US. Japan part of homozygous familial hypercholesterolemai therapy

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6) HDL Modifiers One drug- nicotinic acid- (niacin)

Nicotinamide not active. Mechanism is not via action as vitamin. Very cheap, very effective. However, dose needs to be slowly built up to ~ 4g per day. Can cause prostaglandin-mediated flushing, dizziness, palpitation. Can use aspirin 30 min prior to dose to reduce effects, by minimizing prostaglandin synthesis. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease - The ADMIT Study: A randomized trial JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; SEP 13 2000; v.284, no.10, p.1263-1270 Our study suggests that lipid-modifying dosages of niacin can be safely used in patients with diabetes and that niacin therapy may be considered as an alternative to statin drugs or fibrates for patients with diabetes in whom these agents are not tolerated or fail to sufficiently correct hypertriglyceridemia or low HDL-C levels.

Implies a different mechanism of action There is actually a receptor GPR109A. Activation by nicotinic depresses cAMP formation & lipolysis in adipocytes. Less Free fatty acids released.

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Lower FFA means lower substrates for the liver to make Triglycerides from, less VLDL and TAG. Downstream of VLDL, LDL also goes down.

Exactly why HDL goes up is unclear

Similarity with 3-hydroxybutyrate, a starvation signal (up to 6-8 mM in starvation

3-OH-Bu

Nic

acipimox 1-IPBT-5-CA

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But, GPR109A on dermal macrophages & langerhans cells too!

Causes flushing. Sustained release, ASA and tolerance can all prevent though Aspirin

Still, can cause low compliance, and youd have thought that was that Same receptor in both cell types

These guys did it though

J. Med. Chem., 51 (16), 51015108, 2008. 10.1021/jm800258p 3-(1H-Tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (MK-0354): A Partial Agonist of the Nicotinic Acid Receptor, G-Protein Coupled Receptor 109a, with Antilipolytic but No Vasodilatory Activity in Mice Graeme Semple,* Philip J. Skinner, Tawfik Gharbaoui, Young-Jun Shin, Jae-Kyu Jung, Martin C. Cherrier, Peter J. Webb, Susan Y. Tamura, P. Douglas Boatman, Carleton R. Sage, Thomas O. Schrader, Ruoping Chen, Steven L. Colletti, James R. Tata, M. Gerard Waters, Kang Cheng, Andrew K. Taggart, Tian-Quan Cai, Ester Carballo-Jane, Dominic P. Behan, Daniel T. Connolly, and Jeremy G. Richman Departments of Medicinal Chemistry and Discovery Biology, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, California 92121, Merck Research Laboratories, Rahway, New Jersey 07065 Received March 10, 2008

Figure 1. Effect of acute 5a and nicotinic acid on plasma FFA levels in fasted C57/BL6 mice.

Quantification of the flushing response of nicotinic acid and 5a as measured by laser-Doppler recordings of blood flow in the ear of male C57/BL6 mice.

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Molecule looks like this

But, this doesnt look like a carboxylate, does it? Hint. Tetrazole pKa = 4.4 it is a common replacement for carboxylates in med chem. resonance stabilized anion.

Why can 5a differentiate between GPR109A on adipocytes vs langerhans

1. Different locations of GPR109A Intracellular in adipocytes Extracellular in langerhans

2. The protein is different in different cells 3 Different signalling pathways downstream of GPR109A in different cell types.

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Other ways to avoid flush

Aspirin 30 mins before, Controlled release (niaspan) Laropiprant PGD2 antagonist (tredaptive)

Laropiprant

PGD2

After AIM-HIGH data nicotinic acid may be a busted flush though

Next big target. CETP

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Torcetrapib. Failed Phase 3 due to excess mortality

Anacetrapib and

Dalcetrapib

data out 2012-14

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