title: Structure-activity relationships for 1-phenylbenzimidazoles as selective ATP site inhibitors of the platelet-derived growth factor receptor.
abstract: 1-Phenylbenzimidazoles are shown to be a new class of ATP-site inhibitors of the platelet-derived growth factor receptor (PDGFR). Structure-activity relationships (SARs) are narrow, with closely related heterocycles being inactive. A systematic study of substituted 1-phenylbenzimidazoles showed clear SARs. Substituents at the 4'- and 3'-positions of the phenyl ring are tolerated but do not significantly improve activity, while substituents at the 2'-position abolish it. Substituents in the 2-, 4-, and 7-positions of the benzimidazole ring (with the exception of 4-OH) also abolish activity. Most substituents at the 5- and 6-positions maintain or increase activity, with the 5-OH, 5-OMe, 5-COMe, and 5-CO2Me analogues being >10-fold more potent than the parent 1-phenylbenzimidazole. The 5-OMe analogue was both the most potent inhibitor, and showed the highest selectivity (50-fold) between PDGFR and FGFR isolated enzymes, and also a moderately effective inhibitor (IC50 = 1.9 microM) of PDGF-stimulated PDGFR autophosphorylation in rat aorta smooth muscle cells.
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medicine and Health Sciences, The University of Auckland School of Medicine, Private Bag 92019, Auckland, New Zealand.
authors.forename: B D
authors.initials: BD
authors.lastname: Palmer
authors.forename: J B
authors.initials: JB
authors.lastname: Smaill
authors.forename: M
authors.initials: M
authors.lastname: Boyd
authors.forename: D H
authors.initials: DH
authors.lastname: Boschelli
authors.forename: A M
authors.initials: AM
authors.lastname: Doherty
authors.forename: J M
authors.initials: JM
authors.lastname: Hamby
authors.forename: S S
authors.initials: SS
authors.lastname: Khatana
authors.forename: J B
authors.initials: JB
authors.lastname: Kramer
authors.forename: A J
authors.initials: AJ
authors.lastname: Kraker
authors.forename: R L
authors.initials: RL
authors.lastname: Panek
authors.forename: G H
authors.initials: GH
authors.lastname: Lu
authors.forename: T K
authors.initials: TK
authors.lastname: Dahring
authors.forename: R T
authors.initials: RT
authors.lastname: Winters
authors.forename: H D
authors.initials: HD
authors.lastname: Showalter
authors.forename: W A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D017468:Receptors, Fibroblast Growth Factor; D000255:Adenosine Triphosphate; D017479:Receptors, Platelet-Derived Growth Factor