Substituted 3-(phenylsulfonyl)-1-phenylimidazolidine-2,4-dione derivatives as novel nonpeptide inhibitors of human heart chymase.
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.
Niwata
S
S
Institute for Biomedical Research, Suntory Ltd., Osaka, Japan.
Fukami
H
H
Sumida
M
M
Ito
A
A
Kakutani
S
S
Saitoh
M
M
Suzuki
K
K
Imoto
M
M
Shibata
H
H
Imajo
S
S
Kiso
Y
Y
Tanaka
T
T
Nakazato
H
H
Ishihara
T
T
Takai
S
S
Yamamoto
D
D
Shiota
N
N
Miyazaki
M
M
Okunishi
H
H
Kinoshita
A
A
Urata
H
H
Arakawa
K
K
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
D007093:Imidazoles; D007202:Indicators and Reagents; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D012697:Serine Endopeptidases; D053818:Chymases