title: Synthesis, structure-activity relationships, and pharmacokinetic profiles of nonpeptidic difluoromethylene ketones as novel inhibitors of human chymase.
abstract: Potent human chymase inhibitors with high enzymatic selectivity and satisfactory metabolic stability were obtained by replacing the Val-Pro (P3-P2) dipeptide portion of the previously described inhibitor 1 with a nonpeptidic pyrimidinone skeleton. The potency of the novel compounds was further enhanced by the introduction of carbamoyl-substituted difluoromethylene ketone moieties. The most potent chymase inhibitor of the newly created series was 2u (Y-40018), which had a K(i) of 2.62 nM. Compound 2u possessed high selectivity for human chymase since it lacked significant activity toward other representative human proteolytic enzymes. Moreover its strict specificity for human chymase suggested that 2u strongly inhibited human and canine chymases but not rat and mouse ones. Pharmacokinetic studies in rats and dogs indicated that 2u was absorbed rapidly after oral administration and had satisfactory bioavailability in these experimental animal species (rat, 17%; dog, 32%). In conclusion, 2u is a novel, potent, and orally active chymase inhibitor which would prove very useful in revealing the precise roles of the latter in various pathophysiological processes.
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: M
authors: M
authors: Eda
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; D001682:Biological Availability; D053818:Chymases; D004285:Dogs; D006801:Humans; D006868:Hydrolysis; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; 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: D007659:Ketones; D011480:Protease Inhibitors; D011744:Pyrimidinones; C424918:Y 40018; D012697:Serine Endopeptidases; D053818:Chymases