Synthesis, Structure−Activity Relationships, and Pharmacokinetic Profiles of Nonpeptidic Difluoromethylene Ketones as Novel Inhibitors of Human Chymase

• Published in: Journal of medicinal chemistry Vol. 44; no. 8; pp. 1297 - 1304
• Main Authors: Akahoshi, Fumihiko, Ashimori, Atsuyuki, Sakashita, Hiroshi, Yoshimura, Takuya, Eda, Masahiro, Imada, Teruaki, Nakajima, Masahide, Mitsutomi, Naoko, Kuwahara, Shigeki, Ohtsuka, Tatsuyuki, Fukaya, Chikara, Miyazaki, Mizuo, Nakamura, Norifumi
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.04.2001; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Biological Availability; Chemistry, Medicinal; Chymases; Dogs; Humans; Hydrolysis; Ketones - chemical synthesis; Ketones - chemistry; Ketones - pharmacokinetics; Life Sciences & Biomedicine; Male; Medical sciences; Miscellaneous; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacokinetics; Pyrimidinones - chemical synthesis; Pyrimidinones - chemistry; Pyrimidinones - pharmacokinetics; Rats; Rats, Sprague-Dawley; Science & Technology; Serine Endopeptidases - chemistry; Serine Endopeptidases - metabolism; Structure-Activity Relationship; DESIGN; ENZYME; ESTERS; HUMAN-LEUKOCYTE ELASTASE; MAST-CELL PROTEASE; REFORMATSKY REACTION; ALDEHYDES; RELEASE; HUMAN HEART; DERIVATIVES; Ketoamide; Intravenous administration; Rat; Nitrogen heterocycle; Non peptide compound; Geminal compound; Structure activity relation; Chlorine Organic compounds; Six membered ring; Chemical synthesis; Dog; Fissipedia; Carnivora; Serine endopeptidases; Enzyme; Rodentia; Oral administration; Enzyme inhibitor; In vitro; Chymase; Peptidases; Vertebrata; Mammalia; Animal; Hydrolases; Pyrimidine derivatives; Fluorine Organic compounds; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000497n

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.