Structure-activity relationships for 5-substituted 1-phenylbenzimidazoles as selective inhibitors of the platelet-derived growth factor receptor

Following an earlier discovery of 1-phenylbenzimidazoles as ATP-site inhibi tors of the platelet-derived growth factor receptor (PDGFR), further struct ure-activity relationships for analogues (particularly 5-substituted deriva tives) are reported. The data are consistent with a binding model (construc ted from the homology-modeled structure of the catalytic subunit of the PDG FR using protein kinase A as the template) in which the ligand binds in the relatively narrow ATP site, with the phenyl ring pointing toward the inter ior of the pocket and the 5-position of the benzimidazole ring toward the m outh of the pocket. The narrow binding pocket allows a maximum torsion angl e between the phenyl and benzimidazole rings of about 40 degrees, consisten t with that calculated (43.6 degrees) for the minimum-energy conformation o f the unsubstituted free ligand. The inactivity of 7- or 2'-substituted ana logues is consistent with the greater torsion angle (and thus larger ligand cross-section) of such substituted analogues. There is substantial bulk to lerance for 5-substituents, which protrude out of the mouth of the hydropho bic pocket, with the most effective analogues being those bearing weak base s. On the basis of this model, 5-OR derivatives bearing cationic side chain s were prepared as soluble analogues, and these showed sub-micromolar poten cies against the isolated PDGFR enzyme. They were also moderately effective inhibitors of autophosphorylation of PDGFR in rat aortic vascular smooth m uscle cells, with IC(50)s in the range 0.1-1 mu 1M.