Identification of a Nonpeptidic and Conformationally Restricted Bradykinin B1 Receptor Antagonist with Anti-Inflammatory Activity

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 ∼30% of the gained affinity between “flexible” 4 (K i = 132 nM) and “rigid” 28 (K i = 0.77 nM) to decreased conformational entropy.