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J Am Chem Soc. 2003 Jun 25;125(25):7516-7.

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

Author information

1
Departments of Medicinal Chemistry and Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA. daishi_su@merck.com

Abstract

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.

PMID:
12812482
DOI:
10.1021/ja0353457
[Indexed for MEDLINE]
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