Discovery of novel mesangial cell proliferation inhibitors using a three-dimensional database searching method

A three-dimensional pharmacophore model of mesangial cell (MC) proliferatio n inhibitors was generated from a training set of 4-(diethoxyphosphoryl)met hyl-N-(3-phenyl-[1,2,4]thiadiazol5-yl)benzamide, 2, and its derivatives usi ng the Catalyst/HIPHOP software program. On the basis of the in vitro MC pr oliferation inhibitory activity, a pharmacophore model was generated as sev en features consisting of two hydrophobic regions, two hydrophobic aromatic regions, and three hydrogen bond accepters. Using this model as a three-di mensional query to search the Maybridge database, structurally novel 41 com pounds were identified. The evaluation of MC proliferation inhibitory activ ity using available samples from the 41 identified compounds exhibited over 50% inhibitory activity at the 100 nM range. Interestingly, the newly iden tified compounds by the 3D database searching method exhibited the reduced inhibition of normal proximal tubular epithelial cell proliferation compare d to a training set of compounds.