title: Peptidyl human heart chymase inhibitors. 2. Discovery of highly selective difluoromethylene ketone derivatives with Glu at P3 site.
abstract: Appropriate structural modification of the difluoromethylene ketone derivatives at both P3 and P' positions led us to the discovery of peptidyl human heart chymase inhibitor 12h which shows potent activity with Ki = 6 nM and high selectivity against closely related serine protease bovine alpha-chymotrypsin (chymotrypsin Ki = > 100 microM). Using the compound 12b, a docking study with human heart chymase was carried out to presume probable interactions.
authors.affiliation: Department of Medicinal Chemistry, Green Cross Research Laboratories, Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Eda
authors.forename: A
authors.initials: A
authors.lastname: Ashimori
authors.forename: F
authors.initials: F
authors.lastname: Akahoshi
authors.forename: T
authors.initials: T
authors.lastname: Yoshimura
authors.forename: Y
authors.initials: Y
authors.lastname: Inoue
authors.forename: C
authors.initials: C
authors.lastname: Fukaya
authors.forename: M
authors.initials: M
authors.lastname: Nakajima
authors.forename: H
authors.initials: H
authors.lastname: Fukuyama
authors.forename: T
authors.initials: T
authors.lastname: Imada
authors.forename: S
authors.initials: S
authors.lastname: Takai
authors.forename: N
authors.initials: N
authors.lastname: Shiota
authors.forename: M
authors.initials: M
authors.lastname: Miyazaki
authors.forename: N
authors.initials: N
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D002417:Cattle; D053818:Chymases; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D018698:Glutamic Acid; D006801:Humans; D007202:Indicators and Reagents; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008968:Molecular Conformation; D015394:Molecular Structure; D009206:Myocardium / Q000201:enzymology*; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012984:Software; D013329:Structure-Activity Relationship
chemical_list: D007202:Indicators and Reagents; D007659:Ketones; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; C116628:tert-butoxycarbonyl-glutamyl-prolyl-phenylalanyl (((2-carboxyphenyl)amino)carbonyl)difluoromethylene ketone; D018698:Glutamic Acid; D012697:Serine Endopeptidases; D002918:Chymotrypsin; D053818:Chymases