Identification of a stable chymase inhibitor using a pharmacophore-Based database search.
In general, serine protease chymase inhibitors readily decompose in plasma. We previously found that thiazolidine-2,4-dione and thiadiazole derivatives are also unstable. Using a pharmacophore-based database search, we identified a benzo[b]thiophen-2-sulfonamide derivative as a stable chymase inhibitor. Finding a lead compound with adequate activity and stability by a pharmacophore-based approach is more efficient than modifying an unstable compound to reduce its instability without simultaneously decreasing its inhibitory activity. Our pharmacophore model of chymase inhibitors suggests that the two hydrophobic interactions in the S1 and S1' regions and the two H-bonding interactions between them play important roles in chymase inhibitors.
Koide
Yuuki
Y
Drug Research Department, Tokyo Research Laboratories, TOA EIYO Ltd., 2-293-3 Amanuma, Saitama 330-0834, Japan. koide.yuuki@toaeiyo.co.jp
Tatsui
Akira
A
Hasegawa
Takeshi
T
Murakami
Akira
A
Satoh
Shoji
S
Yamada
Hideki
H
Kazayama
Shin-ichi
S
Takahashi
Atsuo
A
D000818:Animals; D001665:Binding Sites; D053818:Chymases; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D012697:Serine Endopeptidases / Q000737:chemistry / Q000187:drug effects*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology
D015842:Serine Proteinase Inhibitors; D013830:Thiadiazoles; D013844:Thiazoles; D012697:Serine Endopeptidases; D053818:Chymases