A Comparative Molecular Field Analysis Model for 6-Arylpyrrolo[2,1-d][1,5]benzothiazepines Binding Selectively to the Mitochondrial Benzodiazepine Receptor

A series of 42 6-arylpyrrolo[2,1-d][1,5]benzothiazepines, which we have recently described as selective ligands of the mitochondrial benzodiazepine receptor (MBR) (Fiorini I.; et al. J. Med. Chem. 1994, 37, 1427‒1438), have been investigated using the comparative molecular field analysis (CoMFA) approach. The resulting 3D-QSAR model rationalizes the steric and electronic factors which modulate affinity to the MBR with a cross-validation standard error of 0.648 pIC 50 unit. A set of seven novel pyrrolobenzothiazepine congeners has successively been synthesized and tested. The CoMFA model forecasts the binding affinity values of these new compounds with a prediction standard error of 0.536. © 1994, American Chemical Society. All rights reserved.