title: Substituted 3-(phenylsulfonyl)-1-phenylimidazolidine-2,4-dione derivatives as novel nonpeptide inhibitors of human heart chymase.
abstract: A series of 3-(phenylsulfonyl)-1-phenylimidazolidine-2,4-dione derivatives have been synthesized and evaluated for their ability to selectively inhibit human heart chymase. The structure-activity relationship studies on these compounds gave the following results. The 1-phenyl moiety participates in a hydrophobic interaction where an optimum size is required. At this position, 3,4-dimethylphenyl is the best moiety for inhibiting chymase and showed high selectivity compared with chymotrypsin and cathepsin G. A 3-phenylsulfonyl moiety substituted with hydrogen-bond acceptors such as nitrile and methoxycarbonyl enhances its activity. Molecular-modeling studies on the interaction of 3-[(4-chlorophenyl)sulfonyl]-1-(4-chlorophenyl)-imidazolidine-2,4-dione (29) with the active site of human heart chymase suggested that the 1-phenyl moiety interacts with the hydrophobic P1 pocket, the 3-phenylsulfonyl moiety resides in the S1'-S2' subsites, and the 4-carbonyl of the imidazolidine ring and sulfonyl group interact with the oxyanion hole and the His-45 side chain of chymase, respectively. The complex model is consistent with the structure-activity relationships.
authors.affiliation: Institute for Biomedical Research, Suntory Ltd., Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Niwata
authors.forename: H
authors.initials: H
authors.lastname: Fukami
authors.forename: M
authors.initials: M
authors.lastname: Sumida
authors.forename: A
authors.initials: A
authors.lastname: Ito
authors.forename: S
authors.initials: S
authors.lastname: Kakutani
authors.forename: M
authors.initials: M
authors.lastname: Saitoh
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: M
authors.initials: M
authors.lastname: Imoto
authors.forename: H
authors.initials: H
authors.lastname: Shibata
authors.forename: S
authors.initials: S
authors.lastname: Imajo
authors.forename: Y
authors.initials: Y
authors.lastname: Kiso
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
authors.forename: H
authors.initials: H
authors.lastname: Nakazato
authors.forename: T
authors.initials: T
authors.lastname: Ishihara
authors.forename: S
authors.initials: S
authors.lastname: Takai
authors.forename: D
authors.initials: D
authors.lastname: Yamamoto
authors.forename: N
authors.initials: N
authors.lastname: Shiota
authors.forename: M
authors.initials: M
authors.lastname: Miyazaki
authors.forename: H
authors.initials: H
authors.lastname: Okunishi
authors.forename: A
authors.initials: A
authors.lastname: Kinoshita
authors.forename: H
authors.initials: H
authors.lastname: Urata
authors.forename: K
authors.initials: K
authors.lastname: Arakawa
mesh_terms: D001665:Binding Sites; D053818:Chymases; D003196:Computer Graphics; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009010:Monte Carlo Method; D009206:Myocardium / Q000201:enzymology*; D011487:Protein Conformation; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D007093:Imidazoles; D007202:Indicators and Reagents; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D012697:Serine Endopeptidases; D053818:Chymases