Bioactivation of 2,3-diaminopyridine-containing bradykinin B1 receptor antagonists: irreversible binding to liver microsomal proteins and formation of glutathione conjugates.

The 2,3-diaminopyridine (DAP) moiety was found to represent a core structure essential for the potency of a new series of human bradykinin B(1) receptor antagonists. However, incubation of (14)C-labeled 2,3-DAP derivatives with rat and human liver microsomes resulted in substantial irreversible binding of radioactive material to macromolecules by a process that was NADPH-dependent. Trapping the reactive species with GSH led to significant reduction of the irreversible binding of radioactivity, with concomitant formation of abundant GSH adducts.