Synthesis, structure-activity relationships, and pharmacokinetic profiles of nonpeptidic alpha-keto heterocycles as novel inhibitors of human chymase

We designed nonpeptidic chymase inhibitors based on the structure of a pept idic compound (1) and demonstrated that the combination of a pyrimidinone s keleton as a P-3-P-2 scaffold and heterocycles as P-1 carbonyl-activating g roups can function as a nonpeptidic chymase inhibitor. In particular, intro duction of heterobicycles such as benzoxazole resulted in more potent chyma se-inhibitory activity. Detailed structure-activity relationship studies on the benzoxazole moiety and substituents at the 2-position of the pyrimidin one ring revealed that 2r (Y-40079) had the most, potent chymase-inhibitory activity (K-i = 4.85 nM:). This compound was also effective toward chymase s of nonhuman origin and showed good selectivity for chymases over other pr oteases. Pharmacokinetic studies in rats indicated that 2r was absorbed slo wly after oral administration and showed satisfactory bioavailability (BA) (T-max = 6.0 +/- 2.3 h, BA = 19.3 +/- 6.6%, t(1/2) = 35.7 +/- 13.3 h). In c onclusion, 2r is a novel, potent, and orally active chymase inhibitor which would be a useful tool in elucidating the pathophysiological roles of chym ase.