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 In

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• 作者：Jü ; rgen Maibaum ; Stefan Stutz ; Richard Gö ; schke ; Pascal Rigollier ; Yasuchika Yamaguchi ; Fr&eacute ; d&eacute ; ric Cumin ; Joseph Rahuel ; Hans-Peter Baum ; Nissim-Claude Cohen ; Christian R. Schnell
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：October 4, 2007
• 年：2007
• 卷：50
• 期：20
• 页码：4832 - 4844
• 全文大小：294K
• 年卷期：v.50,no.20(October 4, 2007)
• ISSN：1520-4804

文摘

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