1. Identification of a nonpeptidic and conformationally restricted bradykinin B1 receptor antagonist with anti-inflammatory activity
- Author
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David A. Mareska, Dianna Lester-Zeiner, Randall W. Hungate, Eileen Johnson, Toshi Aya, Leyla Arik, Bobby Riahi, Mark H. Norman, Augustus Kamassah, Jian J. Chen, Gloria Biddlecome, Judy Wang, Christopher H. Fotsch, Paul J. Reider, Jason Brooks Human, Benny C. Askew, Derin C. D'amico, Andras Toro, Burgess Laurence E, Carlo van Staden, Vellarkad N. Viswanadhan, Laird Ellen, Darren Martin Harvey, David E. Clarke, Gordon Ng, James Zhan, Kaustav Biswas, Christopher A. Willoughby, Hideo Suzuki, and Robert D. Groneberg
- Subjects
Models, Molecular ,Stereochemistry ,medicine.drug_class ,Entropy ,Molecular Conformation ,Bradykinin ,Inflammation ,CHO Cells ,Pharmacology ,In Vitro Techniques ,Crystallography, X-Ray ,Capillary Permeability ,chemistry.chemical_compound ,Structure-Activity Relationship ,Cricetulus ,Species Specificity ,Cricetinae ,Drug Discovery ,Chlorocebus aethiops ,medicine ,Animals ,Humans ,Chromans ,Pleurisy ,Lagomorpha ,biology ,Anti-Inflammatory Agents, Non-Steroidal ,Antagonist ,Biological activity ,Stereoisomerism ,Receptor antagonist ,biology.organism_classification ,In vitro ,Extravasation ,Rats ,Bradykinin B1 Receptor Antagonists ,chemistry ,Molecular Medicine ,Rabbits ,medicine.symptom - Abstract
We report the discovery of chroman 28, a potent and selective antagonist of human, nonhuman primate, rat, and rabbit bradykinin B1 receptors (0.4-17 nM). At 90 mg/kg s.c., 28 decreased plasma extravasation in two rodent models of inflammation. A novel method to calculate entropy is introduced and ascribed approximately 30% of the gained affinity between "flexible" 4 (Ki = 132 nM) and "rigid" 28 (Ki = 0.77 nM) to decreased conformational entropy.
- Published
- 2007