Maibaum, Jurgen, Stutz, Stefan, Goschke, Richard, Rigollier, Pascal, Yamaguchi, Yasuchika, Cumin, Frederic, Rahuel, Joseph, Baum, Hans-Peter, Cohen, Nissim-Claude, Schnell, Christian, Fuhrer, Walter, Gruetter, Markus, Schilling, Walter and Wood, Jeanette (2007) Structural modification of the P2' position of 2,7-dialkyl-substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octanecarboxamides: the discovery of aliskiren, a potent nonpeptide human renin inhibitor active after once daily dosing in marmosets. Journal of Medicinal Chemistry, 50 (20). pp. 4832-4844. ISSN 0022-2623

Abstract

Due to its function in the rate limiting initial step of the renin-angiotensin system, renin is a particularly promising target for drugs designed to control hypertension, a growing risk to health worldwide. Despite vast efforts over more than two decades, no orally efficacious renin inhibitor had reached the market. As a result of a structure-based topological design approach, we have identified a novel class of small-molecule inhibitors with good oral blood-pressure lowering effects in primates. Further lead optimization aimed for improvement of in vivo potency and duration of action, mainly by P2' modifications at the hydroxyethylene transition-state isostere. These efforts resulted in the discovery of aliskiren (46, CGP060536B, SPP100), a highly potent, selective inhibitor of renin, demonstrating excellent efficacy in sodium-depleted marmosets after oral administration, with sustained duration of action in reducing dose-dependently mean arterial blood pressure. Aliskiren has recently received regulatory approval by the U.S. Food and Drug Administration for the treatment of hypertension.

Item Type:	Article
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Related URLs:	http://www.ncbi.nlm.nih.gov/sites/entrez...
Date Deposited:	14 Dec 2009 14:00
Last Modified:	31 Jan 2013 01:18
URI:	https://oak.novartis.com/id/eprint/379