IDENTIFICATION OF NOVEL FARNESYL-PROTEIN TRANSFERASE INHIBITORS USING3-DIMENSIONAL DATABASE SEARCHING METHODS

Generation of a three-dimensional pharmacophore model (hypothesis) tha t correlates the biological activity of a series of farnesyl protein t ransferase (FPT) inhibitors, exemplified by the prototype ,6]cyclohept a[1,2-b]pyridin-11-ylidene)piperidine, Sch 44342, 1, with their chemic al structure was accomplished using the three-dimensional quantitative structure-activity relationship (3D-QSAR) software program, Catalyst. On the basis of the in vitro FPT inhibitory activity of a training se t of compounds, a five-feature hypothesis containing four hydrophobic and one hydrogen bond acceptor region was generated. Using this hypoth esis as a three-dimensional query to search our corporate database ide ntified 718 compounds (hits). Determination of the in vitro FPT inhibi tory activity using available compounds from this ''hitlist'' identifi ed five compounds, representing three structurally novel classes, that exhibited in vitro FPT inhibitory activity, IC50 less than or equal t o 5 mu M. From these three classes, a series of substituted dihydroben zothiophenes was selected for further structure-FPT inhibitory activit y relationship studies. The results from these studies is discussed.