The discovery and synthesis of potent zwitterionic inhibitors of renin

被引：9

作者：

Aspiotis, Renee ^{[1
]}

Chen, Austin ^{[1
]}

Cauchon, Elizabeth ^{[1
]}

Dube, Daniel ^{[1
]}

Falgueyret, Jean-Pierre ^{[1
]}

Gagne, Sebastien ^{[1
]}

Gallant, Michel ^{[1
]}

Grimm, Erich L. ^{[1
]}

Houle, Robert ^{[1
]}

Juteau, Helene ^{[1
]}

Lacombe, Patrick ^{[1
]}

Laliberte, Sebastien ^{[1
]}

Levesque, Jean-Francois ^{[1
]}

MacDonald, Dwight ^{[1
]}

McKay, Dan ^{[1
]}

Percival, M. David ^{[1
]}

Roy, Patrick ^{[1
]}

Soisson, Stephen M. ^{[2
]}

Wu, Tom ^{[1
]}

机构：

[1] Merck Frosst Ctr Therapeut Res, Pointe Claire, PQ H9R 4P8, Canada

[2] Merck Res Labs, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 08期

关键词：

Renin; Hypertension; Piperidine; Zwitterion; hERG; CYP3A4; PEPTIDASE-IV INHIBITORS; AMINO ACID SEQUENCE; SUBSTITUTED PIPERIDINES; OPTIMIZATION; DESIGN; SERIES; HERG; ALISKIREN; 3A4;

D O I：

10.1016/j.bmcl.2011.02.067

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The incorporation of a carboxylic acid within in a series of 3-amido-4-aryl substituted piperidines (represented by general structure 32) led to the discovery of potent, zwitterionic, renin inhibitors with improved off-target profiles (CYP3A4 time-dependent inhibition and hERG affinity) relative to analogous non-zwitterionic inhibitors of the past (i.e., 3). Strategies to address the oral absorption of these zwitterions are also discussed within. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：2430 / 2436

页数：7

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