Small molecule antagonists of the bradykinin B1 receptor

Screening Pharmacopeia's encoded combinatorial libraries has led to the ide ntification of potent, selective, competitive antagonists at the bradykinin B1 receptor. Libraries were screened using a displacement assay of [H-3]-d es-Arg (10)-kallidin ([H-3]-dAK) at IMR-90 cells expressing an endogenous h uman B1 receptor (B-max = 20,000 receptors/cell, K-D = 0.5 +/- 0.1 nM) or a gainst membranes from 293E cells expressing a recombinant human B1 receptor (B-max = 8,000 receptors/cell, K-D = 0.5 +/- 0.3 nM). Compound PS020990, a n optimized, representative member from the class of compounds, inhibits sp ecific binding of H-3-dAK at IMR-90 cells with a K-1 of 6 +/- 1 nM. The com pound inhibits dAK-induced phosphatidyl inositol turnover( K-Bapp = 0.4 +/- 0.2 nM) and calcium mobilization (K-Bapp = 17 +/- 2 nM) in IMR-90 cells. C ompounds from the lead series are inactive at the B2 receptor and are > 100 0-fold specific for BI vs. a variety of other receptors, ion channels and e nzymes. PS020990 and other related chemotypes therefore offer an excellent opportunity to explore further the role of B1 receptors in disease models a nd represent a potential therapeutic avenue. (C) 1999 Elsevier Science B.V. All rights reserved.