Novel 2,7-Dialkyl-Substituted 5(S)-Amino-4(S)-hydroxy-8-phenyl-octanecarboxamide Transition State Peptidomimetics Are Potent and Orally Active Inhibitors of Human Renin

详细信息    查看全文

• 作者：Richard Gö ; schke ; Stefan Stutz ; Vittorio Rasetti ; Nissim-Claude Cohen ; Joseph Rahuel ; Pascal Rigollier ; Hans-Peter Baum ; Peter Forgiarini ; Christian R. Schnell ; Trixie Wagner ; Markus G. Gruetter
• 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：4818 - 4831
• 全文大小：433K
• 年卷期：v.50,no.20(October 4, 2007)
• ISSN：1520-4804

文摘

The action of renin is the rate-limiting step of the renin-angiotensin system (RAS), a key regulator of bloodpressure. Effective renin inhibitors directly block the RAS entirely at source and, thus, may provide a vitalweapon for hypertension therapy. Our efforts toward identifying novel small-molecule peptidomimetic renininhibitors have resulted in the design of transition-state isosteres such as 1 bearing an all-carbon 8-phenyl-octanecarboxamide framework. Optimization of the extended P3 portion of 1 and extensive P2' modificationsprovided analogues with improved in vitro potencies in the presence of plasma. X-ray resolution of rh-renin/38a in the course of SAR work surprisingly unveiled the exploitation of a previously unexploredpocket (S3^sp) important for strong binding affinities. Several inhibitors demonstrated oral efficacy in sodium-depleted marmosets. The most potent, 38a, induced dose-dependently a pronounced reduction in mean arterialblood pressure, paralleled by complete blockade of active plasma renin, up to 8 h post-dose. Oralbioavailability of 38a was 16% in marmosets.