title: Discovery of novel mesangial cell proliferation inhibitors using a three-dimensional database searching method.
abstract: A three-dimensional pharmacophore model of mesangial cell (MC) proliferation inhibitors was generated from a training set of 4-(diethoxyphosphoryl)methyl-N-(3-phenyl-[1,2,4]thiadiazol-5-yl)benzamide, 2, and its derivatives using the Catalyst/HIPHOP software program. On the basis of the in vitro MC proliferation inhibitory activity, a pharmacophore model was generated as seven features consisting of two hydrophobic regions, two hydrophobic aromatic regions, and three hydrogen bond acceptors. Using this model as a three-dimensional query to search the Maybridge database, structurally novel 41 compounds were identified. The evaluation of MC proliferation inhibitory activity using available samples from the 41 identified compounds exhibited over 50% inhibitory activity at the 100 nM range. Interestingly, the newly identified compounds by the 3D database searching method exhibited the reduced inhibition of normal proximal tubular epithelial cell proliferation compared to a training set of compounds.
authors: Medicinal Chemistry Laboratory, Nutrition Research Institute, Otsuka Pharmaceutical Factory, Inc., Tateiwa, Muya-cho, Naruto, Tokushima 772-8601, Japan. kurogiys@otsukakj.co.jp
authors: Y
authors: Y
authors: Kurogi
authors: K
authors: K
authors: Miyata
authors: T
authors: T
authors: Okamura
authors: K
authors: K
authors: Hashimoto
authors: K
authors: K
authors: Tsutsumi
authors: M
authors: M
authors: Nasu
authors: M
authors: M
authors: Moriyasu
mesh_terms: D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002384:Catalysis; D002455:Cell Division; D002478:Cells, Cultured; D020650:Combinatorial Chemistry Techniques; D016208:Databases, Factual; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001549:Benzamides; D013830:Thiadiazoles