An update on non-peptide angiotensin receptor antagonists and related RAAS modulators

The renin-angiotensin-aldosterone-system (RAAS) is an important regulator of blood pressure and fluid-electrolyte homeostasis. RAAS has been implicated in pathogenesis of hypertension, congestive heart failure, and chronic renal failure. Aliskiren is the first non-peptide orally active renin inhibitor approved by FDA. Angiotensin Converting Enzyme (ACE) Inhibitors are associated with frequent side effects such as cough and angio-oedema. Recently, the role of ACE2 and neutral endopeptidase (NEP) in the formation of an important active metabolite/mediator of RAAS, ang 1-7, has initiated attempts towards development of ACE2 inhibitors and combined ACE/NEP inhibitors. Furukawa and colleagues developed a series of low molecular weight nonpeptide imidazole analogues that possess weak but selective, competitive AT, receptor blocking property. Till date, many compounds have exhibited promising AT, blocking activity which cause a more complete RAAS blockade than ACE inhibitors. Many have reached the market for alternative treatment of hypertension, heart failure and diabetic nephropathy in ACE inhibitor intolerant patients and still more are waiting in the queue. But, the hallmark of this area of drug research is marked by a progress in understanding molecular interaction of these blockers at the AT, receptor and unraveling the enigmatic influence of AT(2) receptors on growth/anti-growth, differentiation and the regeneration of neuronal tissue. Different modeling strategies are underway to develop tailor made molecules with the best of properties like Dual Action (Angiotensin And Endothelin) Receptor Antagonists (DARA), ACE/NEP inhibitors, triple inhibitors AT(2) agonists, AT(1)/TxA(2) antagonists, balanced AT(1)/AT(2) antagonists, and nonpeptide renin inhibitors. This abstract gives an overview of these various angiotensin receptor antagonists. (c) 2007 Elsevier Inc. All rights reserved.