Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

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.

Maibaum, Jurgen and Stutz, Stefan and Goschke, Richard and Rigollier, Pascal and Yamaguchi, Yasuchika and Cumin, Frederic and Rahuel, Joseph and Baum, Hans-Peter and Cohen, Nissim-Claude and Schnell, Christian and Fuhrer, Walter and Gruetter, Markus and 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
Related URLs:
Additional Information: archiving not formally supported by this publisher
Related URLs:
Date Deposited: 14 Dec 2009 14:00
Last Modified: 31 Jan 2013 01:18
URI: https://oak.novartis.com/id/eprint/379

Search

Email Alerts

Register with OAK to receive email alerts for saved searches.