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.
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Authors | Dai-Shi Su, M Kristine Markowitz, Robert M DiPardo, Kathy L Murphy, C Meacham Harrell, Stacy S O'Malley, Richard W Ransom, Raymond S L Chang, Sookhee Ha, Fred J Hess, Douglas J Pettibone, Glenn S Mason, Susan Boyce, Roger M Freidinger, Mark G Bock |
Journal | Journal of the American Chemical Society
(J Am Chem Soc)
Vol. 125
Issue 25
Pg. 7516-7
(Jun 25 2003)
ISSN: 0002-7863 [Print] United States |
PMID | 12812482
(Publication Type: Journal Article)
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Chemical References |
- Analgesics
- Bradykinin Receptor Antagonists
- Quinoxalines
- Receptor, Bradykinin B1
- Receptors, Bradykinin
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Topics |
- Analgesics
(chemistry, pharmacology)
- Animals
- Binding Sites
- Bradykinin Receptor Antagonists
- Dogs
- Humans
- Kinetics
- Models, Molecular
- Mutagenesis, Site-Directed
- Pain Measurement
(drug effects)
- Quinoxalines
(chemistry, pharmacology)
- Rabbits
- Rats
- Receptor, Bradykinin B1
- Receptors, Bradykinin
(chemistry, genetics, metabolism)
- Structure-Activity Relationship
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