Synthesis, Structure−Activity Relationships, and Pharmacokinetic Profiles of Nonpeptidic α-Keto Heterocycles as Novel Inhibitors of Human Chymase

We designed nonpeptidic chymase inhibitors based on the structure of a peptidic compound (<BO>1</BO>) and demonstrated that the combination of a pyrimidinone skeleton as a P<INF>3</INF>−P<INF>2</INF> scaffold and heterocycles as P<INF>1</INF> carbonyl-activating groups can function as a nonpeptidic chymase inhibitor. In particular, introduction of heterobicycles such as benzoxazole resulted in more potent chymase-inhibitory activity. Detailed structure−activity relationship studies on the benzoxazole moiety and substituents at the 2-position of the pyrimidinone ring revealed that <BO>2r</BO> (Y-40079) had the most potent chymase-inhibitory activity (K<INF>i</INF> = 4.85 nM). This compound was also effective toward chymases of nonhuman origin and showed good selectivity for chymases over other proteases. Pharmacokinetic studies in rats indicated that <BO>2r</BO> was absorbed slowly after oral administration and showed satisfactory bioavailability (BA) (T<INF>max</INF> = 6.0 ± 2.3 h, BA = 19.3 ± 6.6%, t<INF>1/2</INF> = 35.7 ± 13.3 h). In conclusion, <BO>2r</BO> is a novel, potent, and orally active chymase inhibitor which would be a useful tool in elucidating the pathophysiological roles of chymase.