title: Synthesis, structure-activity relationships, and pharmacokinetic profiles of nonpeptidic alpha-keto heterocycles as novel inhibitors of human chymase.
abstract: We designed nonpeptidic chymase inhibitors based on the structure of a peptidic compound (1) and demonstrated that the combination of a pyrimidinone skeleton as a P3-P2 scaffold and heterocycles as P1 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 2r (Y-40079) had the most potent chymase-inhibitory activity (K(i) = 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 2r was absorbed slowly 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 conclusion, 2r is a novel, potent, and orally active chymase inhibitor which would be a useful tool in elucidating the pathophysiological roles of chymase.
authors: Drug Discovery Laboratories, Welfide Corporation, 2-25-1, Shodai-Ohtani, Hirakata, Osaka 573-1153, Japan. akahoshi@welfide.co.jp
authors: F
authors: F
authors: Akahoshi
authors: A
authors: A
authors: Ashimori
authors: H
authors: H
authors: Sakashita
authors: T
authors: T
authors: Yoshimura
authors: T
authors: T
authors: Imada
authors: M
authors: M
authors: Nakajima
authors: N
authors: N
authors: Mitsutomi
authors: S
authors: S
authors: Kuwahara
authors: T
authors: T
authors: Ohtsuka
authors: C
authors: C
authors: Fukaya
authors: M
authors: M
authors: Miyazaki
authors: N
authors: N
authors: Nakamura
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001682:Biological Availability; D053818:Chymases; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D001583:Benzoxazoles; D011480:Protease Inhibitors; D011744:Pyrimidinones; C424917:Y 40079; D012697:Serine Endopeptidases; D053818:Chymases