Discovery of a potent, non-peptide bradykinin B1 receptor antagonist

被引：81

作者：

Su, DS ^{[1
]}

Markowitz, MK

DiPardo, RM

Murphy, KL

Harrell, CM

O'Malley, SS

Ransom, RW

Chang, RSL

Ha, S

Hess, FJ

Pettibone, DJ

Mason, GS

Boyce, S

Freidinger, RM

Bock, MG

机构：

[1] Merck Res Labs, Dept Med Chem, W Point, PA 19486 USA

[2] Merck Res Labs, Dept Neurosci, W Point, PA 19486 USA

[3] Merck Res Labs, Neurosci Res Ctr, Harlow CM20 2QR, Essex, England

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2003年 / 125卷 / 25期

关键词：

D O I：

10.1021/ja0353457

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Bradykinin (BK) plays an important role in the pathophysiological processes accompanying pain and inflammation. Selective bradykinin B1 receptor antagonists have been shown to be anti-nociceptive in animal models and could be novel therapeutic agents for the treatment of pain and inflammation. We have explored chemical modifications in a series of dihydroquinoxalinone sulfonamides to evaluate the effects of various structural changes on biological activity. The optimization of a screening lead compound, facilitated by a homology model of the BK B1 receptor, culminated in the discovery of a potent human BK B1 receptor antagonist. Results from site-directed mutagenesis studies and experiments in an animal pain model are presented. Copyright © 2003 American Chemical Society.

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页码：7516 / 7517

页数：2

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