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
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.
引用
收藏
页码:7516 / 7517
页数:2
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