Dr.

Dhiren M Pranami

Scope of the problem Renin Angiotensin Aldosterone System Existing treatment Medical need Recent advances Summary

One billion people worldwide suffer from hypertension and it is expected that their number will rise by 60% within the coming 15 years Coronary atherosclerosis and acute MI ranked as the top two diagnoses treated in US hospitals The American Heart Association estimated that heart failure cost the U.S. healthcare system more than $37 billion in 2007, including direct costs of $20 billion


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Renin:

Secreted by the juxtaglomerular cells in Kidney

Is an enzyme of 347 AA Release is regulated by cAMP Changes in secretion is in response to changes in renal arterial pressure, sympathetic signals Its substrate is angiotensinogen

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Angiotensinogen: Glycoprotein synthesized and secreted into the bloodstream by the liver Angiotensin converting enzyme (ACE)/kinases II converts angiotensin I to II (vasoconstrictor) Principal site of its action is vascular epithelium

Inhibited by synthetically produced Captopril

Aldosterone: Synthesised in the glomerulosa cells of the adrenal gland from corticosterone by the enzyme 11--hydroxylase (CYP11B2), also called aldosterone synthase Regulation of Aldosterone

Angiotensin II and III stimulate aldosterone release Changes in volume ( long Negative feedback loop) Inhibition of renin secretion by angiotensin II (short negative feedback loop) Endothelin and vasopressin stimulate aldosterone secretion ANP is a potent inhibitor

In contrast to the discussed RAAS components, which all contribute to the pathology of hypertension or end organ damage, RAAS additionally harbours a protective arm active hormones (angiotensin-(1-7)), enzymes (ACE2) and receptors (AT2 and Mas) mediating tissueprotective actions

Ang-(1-7)
Generated from Ang II by the ACE2 and interacts with its receptor Mas. Heptapeptide counteract most of the classical actions of Ang II being antihypertensive, antihypertrophic, antifibrotic and improving the metabolic status

AT2 receptor
Activated by Ang II Interfere with AT1 receptor-coupled actions

Also with cytokines and growth factors thereby acting anti-inflammatory, antiproliferative, antifibrotic, anti-apoptotic and neurodegenerative

ACE: Angiotensin-convering enzyme; NEP: Neutral endopeptidase; (P)RR: (Pro)renin receptor; Mas: Mas receptor

Originally isolated from the venome of the Brazilian snake Bothrops jararaca Captopril, Enalapril, Lisinopril, Perindopril, Cilazapril, Benazepril, Quinapril, Fosinopril, Ramipril Major problem
Chronic cough discontinuation of treatment in up to 20%. Angioedema in < 0.1% very rare is a potentially life threatening

Both side effects, cough and angioedema caused by accumulation of bradykinin and other kinins, which are cleaved and inactivated by ACE.

The HOPE (Heart Outcomes Prevention Evaluation) study in 2000

landmark study in the history of cardiovascular drug development Showing that pharmacological interference with RAAS by ACE inhibition with ramipril reduced mortality in patients at cardiovascular risk more than would have been expected by the modest fall in blood pressure in the almost normotensive study population

Despite a still ongoing discussion about the relative role of blood pressure reductions in this study, these results suggest an additional, non-blood pressurerelated benefit of RAAS inhibitors beyond their pure antihypertensive action.

Losartan, Telmisartan, Candesartan, Valsartan, Eprosartan, Irbesartan, Olmesartan, Zolasartan No interaction with kinin metabolism typical adverse reactions of ACE inhibitors would not occur in patients treated with ARBs Incidence of chronic cough turned out to be at placebo level, while angioedema still seems to occur, although at much lower rate than with ACE inhibitors

Series of large-scale clinical trials showed effectiveness in chronic heart failure, diabetic kidney disease and retinopathy
Since ARBs were superior to other antihypertensives in reducing end points such as death, MI or stroke despite an equal reduction in blood pressure, it is speculated that ARBs may have favourable features extending their antihypertensive effects. Such features may be explained by reactively increased renin and Ang II levels, which in turn stimulate the unopposed AT2 receptors. AT2 receptors have been described to oppose the AT1 receptor and act as tissue-protective agents.

Leonard Skeggs, who wrote in 1957 Since renin

is the initial and rate-limiting substance in the renin-hypertension system it would seem that this last approach (i.e., inhibition of renin) would be the most likely to succeed
Recently, a first renin inhibitor, aliskiren, has been approved for the treatment of hypertension. Aliskiren is currently tested in several large-scale clinical trials for tissue-protective properties beyond its antihypertensive effect

In RALES (Randomized Aldosterone Evaluation Study), the addition of spironolactone to conventional therapy (including ACE inhibition) further markedly reduced morbidity and mortality in patients with severe heart failure However, the use of spironolactone is limited by its low MR selectivity leading to adverse progesterone and testosterone dependent side effects, such as gynaecomastia, menstrual irregularities and loss of libido

Eplerenone a novel aldosterone receptor blocker In EPHESUS (Eplerenone Heart Failure Efficacy and Survival Study), a study with similar design to RALES, eplerenone reduced morbidity and mortality in heart failure patients when added to standard medication However, in contrast to spironolactone, it has 100 - 1000 lower affinity to testosterone and progesterone receptors, meaning less pronounced sexual side effects

Almost one billion people worldwide suffer from hypertension and it is expected that their number will rise by 60% within the coming 15 years Although several potent antihypertensives are already on the market, in only about 25% of patients the reduction of blood pressure meets levels recommended by current guidelines There is a certain percentage of patients in which hypertension cannot be controlled with current treatments, not even with the combination of three to four antihypertensive. They are suffering from socalled resistant hypertension.

ACE: Angiotensin-convering enzyme; NEP: Neutral endopeptidase; (P)RR: (Pro)renin receptor; Mas: Mas receptor

Fimasartan and azilsartan pure AT1 blockers

LCZ696 not only antagonises AT1 but also blocks NEP

The stabilisation of cardioprotective kinins and natriuretic peptides by NEP inhibition contributes to the protective actions of an AT1 antagonist LCZ696 compared with a classical AT1 antagonist in a recent clinical trial and has shown higher efficiency in blood pressure reduction without additional adverse effects NEP inhibition remains problematic, since it has been shown that NEP is responsible for the degradation of amyloid peptides in Alzheimers disease and since NEP-deficient mice become obese at higher age, the reason for which is unknown. Thus, severe long-term side effects of NEP inhibition cannot be ruled out.

TRV-120027 first example of a biased agonist for a G-protein coupled receptor which has entered clinical trials Agonists are referred to as biased when they select which signaling pathways become activated on binding to the receptor Action is based on the stabilisation of a certain conformation of the AT1 receptor which only allows signalling through -arrestin and the internalisation and degradation of the receptor In animal experiments, TRV-120027 reduced mean arterial pressure, as did the unbiased AT1 antagonists and it increased cardiac performance These effects were explained by a antagonism of the AT1 receptor reducing blood pressure but at the same time by an activation of the extracellular signal-regulated kinases (ERK) 1/2 and NO signalling pathways increasing cardiac stroke volume

Another attempt to increase potency of ARBs is the combination of an approved ARB with NO-releasing entities in one molecule NO is known to act vasodilatory thus lowering blood pressure. In addition, it also has tissue protective properties Both features may be additive to similar actions of ARBs/ACE inhibitors thus potentiating their bloodpressure lowering effects and also tissue-protective actions beyond the pure antihypertensive effect. NO-releasing ARBs/ACE inhibitors have entered Phase I clinical evaluation

Just one drug has entered the market, aliskiren. All previous attempts have been hampered by the fact that DRIs all seem to have a very low oral bioavailability (oral bioavailability of aliskiren is 2 - 3%).

One other substance, VTP-27999 has just successfully completed a Phase I clinical trial and a Phase IIb trial is planned for the end of 2011.
However, indication is not hypertension as for aliskiren, but chronic kidney diseases induced by diabetes or hypertension.

A novel approach is to move from receptor blockade to the inhibition of aldosterone synthesis. At least three compounds identified: FAD286, LCI699 and SPP2745 FAD286 inhibits aldosterone synthase reduced blood pressure and attenuated myocardial and renal targetorgan damage SPP2745 suppressed aldosterone levels and also provided cardio-, reno- and vasculo-protective effects even when in combination with conventional therapy LCI699 suppressed aldosterone levels and lowered blood pressure by 4.1 mm Hg in 14 hypertensive patients

The first compound, which has entered clinical trials and interacts with the beneficial arm of RAAS, the ACE2/Ang(1-7)/Mas axis, is APN01 APN01 is recombinant human ACE2 and is indicated for heart failure and additionally for acute respiratory distress syndrome It has been shown, that Ang II is detrimental and Ang-(17) is beneficial in acute lung diseases. Since ACE2 destroys Ang II and generates Ang-(1-7), it became a novel therapeutic principle for these diseases. APN01 successfully completed phase I clinical trial

Actions mediated by the AT2 receptor are also opposing those of the AT1 receptor. Thus, in order to make use of the favourable effects coupled to the AT2 receptor, a specific AT2 agonist is needed. Such an agonist with drug-like properties has been designed and synthesised in 2004 and is currently in preclinical development showing tissue-protective features in various disease models.

Activity of RAAS can be chronically downregulated through elimination of critical components of RAAS by vaccination against these respective components Conjugate vaccine, CYT006-AngQb composed of Ang II chemically linked to recombinant virus like particles CYT006-AngQb underwent a successful combined Phase I and Phase II study performed in 2005/2006 Second RAAS-based vaccine termed ATV (angiotensin therapeutic vaccine) consists of an Ang I peptide conjugated to carrier protein KLH (keyhole limpet haemocyanin) This vaccine underwent a successful Phase I study and lowered blood pressure in salt-depleted healthy volunteers but not in hypertensive patients

Emerging drugs which target the renin-angiotensinaldosterone system Expert Opin. Emerging Drugs (2011) Goodman & Gilman's The Pharmacological Basis of Therapeutics Supplement to journal of managed care pharmacy vol-13. No.8, S-b