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
2007; American Chemical Society; Volume: 50; Issue: 20 Linguagem: Inglês
10.1021/jm070316i
ISSN1520-4804
AutoresJürgen Maibaum, Stefan Stutz, Richard Göschke, Pascal Rigollier, Yasuchika Yamaguchi, Frédéric Cumin, Joseph Rahuel, Hans-Peter Baum, Nissim-Claude Cohen, Christian Schnell, Walter Fuhrer, M.G. Gruetter, Walter Schilling, Jeanette M. Wood,
Tópico(s)Renin-Angiotensin System Studies
ResumoDue 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.
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