Design and synthesis of potent, isoxazole-containing renin inhibitors

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• 作者：Pierre-André ; Fournier ; ^{pierre-andre_fournier@merck.com} ; Mé ; lissa Arbour ; Elizabeth Cauchon ; Austin Chen ; Amandine Chefson ; Yves Ducharme ; Jean-Pierre Falgueyret ; Sé ; bastien Gagné ; Erich Grimm ; Yongxin Han ; Robert Houle ; Patrick Lacombe ; Jean-Franç ; ois Lé ; vesque ; Dwight MacDonald ; Bruce Mackay ; Dan McKay ; M. David Percival ; Yeeman Ramtohul ; René ; St-Jacques ; Sylvie Toulmond
• 关键词：Renin ; Inhibitor ; Anti-hypertensive
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 April, 2012
• 卷：22
• 期：8
• 页码：2670-2674
• 文件大小：459 K

摘要

The design and optimization of a novel isoxazole S₁ linker for renin inhibitor is described herein. This effort culminated in the identification of compound 18, an orally bioavailable, sub-nanomolar renin inhibitor even in the presence of human plasma. When compound 18 was found to inhibit CYP3A4 in a time dependent manner, two strategies were pursued that successfully delivered equipotent compounds with minimal TDI potential.