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.
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Bradykinin B1 Receptor Antagonists*
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CHO Cells
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Capillary Permeability / drug effects
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Chlorocebus aethiops
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Chromans / chemical synthesis*
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Chromans / pharmacokinetics
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Chromans / pharmacology
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Cricetinae
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Cricetulus
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Crystallography, X-Ray
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Entropy
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Humans
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In Vitro Techniques
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Models, Molecular
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Molecular Conformation
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Pleurisy / drug therapy
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Rabbits
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Rats
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Species Specificity
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Bradykinin B1 Receptor Antagonists
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Chromans