Chapter 7. Anglotensln / Renln Modulators

TL;DR: This chapter summarizes the recent drug discovery and development of non-peptidic angiotensin II (AII) receptor antagonists in the renin-angiotens in system area.

Abstract: Publisher Summary Angiotensin-converting enzyme (ACE) inhibitors have led the way with impressive efficacy for the treatment of hypertension and heart failure. This chapter summarizes the recent drug discovery and development of non-peptidic angiotensin II (AII) receptor antagonists in the renin-angiotensin system area. The antihypertensive efficacy of ACE inhibitors is well established, and new data on their therapeutic benefit in heart failure has been impressive. Renin inhibitors have been reviewed recently, and an overview of recent clinical results has appeared. In vivo pharmacology and clinical studies of the potent inhibitor ES-8891 have been reviewed. This inhibitor suppressed renin gene expression and blocked renin secretion. New work continues to focus on improving oral bioavailability of renin inhibitors by modifying their physical properties and reducing their peptide character. Introduction to heterocycles or hydrophilic amino or phosphonate groups at the carboxy-terminus has yielded potent inhibitors. Conformationally-constrained inhibitors continue to be reported. Inhibitors that incorporate carboxy-terminal lactam and oxazolidinone constraints are highly potent. Peptide analogs of AII continue to provide important insights into how AII interacts with its two binding sites, the AT 1 and AT 2 receptors. The development of potent, orally-active non-peptidic AII receptor antagonists from a series of benzyl-substituted imidazoles, such as S8308, has been reviewed. The availability of non-peptidic antagonists has permitted the study of AII receptor subtypes in numerous tissues. Antagonists that incorporate variations of the biphenyltetrazole element have also been reported. Exciting progress has been made in the molecular characterization of AII receptors. In vivo pharmacology of losartan has been reviewed. Other antagonists that have shown efficacy in blocking the pressor response to AII or in models of hypertension include DuP532, SK&F-108566, L-158,809, GR-117289, D-8731, R-47436, and BIBS39. New potential utilities for blockers of the renin-angiotensin system continue to be explored.