Structure−Activity Relationships for 5-Substituted 1-Phenylbenzimidazoles as Selective Inhibitors of the Platelet-Derived Growth Factor Receptor

• Published in: Journal of medicinal chemistry 1999-07, Vol.42 (13), p.2373-2382
• Main Authors: Palmer, Brian D, Kraker, Alan J, Hartl, Brian G, Panopoulos, Athanasia D, Panek, Robert L, Batley, Brian L, Lu, Gina H, Trumpp-Kallmeyer, Susanne, Showalter, H. D. Hollis, Denny, William A
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Animals; Antineoplastic agents; Aorta - cytology; Aorta - drug effects; Aorta - metabolism; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - metabolism; Benzimidazoles - pharmacology; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; General aspects; Humans; In Vitro Techniques; Ligands; Medical sciences; Models, Molecular; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Pharmacology. Drug treatments; Phosphorylation; Protein-Tyrosine Kinases - antagonists & inhibitors; Rats; Receptors, Platelet-Derived Growth Factor - antagonists & inhibitors; Receptors, Platelet-Derived Growth Factor - metabolism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980658b

Following an earlier discovery of 1-phenylbenzimidazoles as ATP-site inhibitors of the platelet-derived growth factor receptor (PDGFR), further structure−activity relationships for analogues (particularly 5-substituted derivatives) are reported. The data are consistent with a binding model (constructed from the homology-modeled structure of the catalytic subunit of the PDGFR 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 interior of the pocket and the 5-position of the benzimidazole ring toward the mouth of the pocket. The narrow binding pocket allows a maximum torsion angle between the phenyl and benzimidazole rings of about 40°, consistent with that calculated (43.6°) for the minimum-energy conformation of the unsubstituted free ligand. The inactivity of 7- or 2‘-substituted analogues is consistent with the greater torsion angle (and thus larger ligand cross-section) of such substituted analogues. There is substantial bulk tolerance for 5-substituents, which protrude out of the mouth of the hydrophobic pocket, with the most effective analogues being those bearing weak bases. On the basis of this model, 5-OR derivatives bearing cationic side chains were prepared as soluble analogues, and these showed sub-micromolar potencies against the isolated PDGFR enzyme. They were also moderately effective inhibitors of autophosphorylation of PDGFR in rat aortic vascular smooth muscle cells, with IC50s in the range 0.1−1 μM.