Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 1999-07, Vol.42 (13), p.2373-2382

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

1999

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.