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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.

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Departments of Medicinal Chemistry and Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA.


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.

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