Design and optimization of a substituted amino propanamide series of renin inhibitors for the treatment of hypertension

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• 作者：Austin Chen ; Christopher Bayly ; Olivier Bezenç ; on ; Sylvia Richard-Bildstein ; Daniel Dubé ; Laurence Dubé ; Sé ; bastien Gagné ; Michel Gallant ; Mireille Gaudreault ; Erich Grimm ; Robe
• 关键词：Renin ; Inhibitor ; Anti-hypertensive ; Protease
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2010
• 出版时间：1 April 2010
• 年：2010
• 卷：20
• 期：7
• 页码：2204-2209
• 全文大小：608 K

文摘

The discovery and SAR of a new series of substituted amino propanamide renin inhibitors are herein described. This work has led to the preparation of compounds with in vitro and in vivo profiles suitable for further development. Specifically, challenges pertaining to oral bioavailability, covalent binding and time-dependent CYP 3A4 inhibition were overcome thereby culminating in the identification of compound 50 as an optimized renin inhibitor with good efficacy in the hypertensive double-transgenic rat model.