Structure-activity relationships for 1-phenylbenzimidazoles as selective ATP site inhibitors of the platelet-derived growth factor receptor.
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.
Palmer
B D
BD
Auckland Cancer Society Research Centre, Faculty of Medicine and Health Sciences, The University of Auckland School of Medicine, Private Bag 92019, Auckland, New Zealand.
Smaill
J B
JB
Boyd
M
M
Boschelli
D H
DH
Doherty
A M
AM
Hamby
J M
JM
Khatana
S S
SS
Kramer
J B
JB
Kraker
A J
AJ
Panek
R L
RL
Lu
G H
GH
Dahring
T K
TK
Winters
R T
RT
Showalter
H D
HD
Denny
W A
WA
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
D001562:Benzimidazoles; D017468:Receptors, Fibroblast Growth Factor; D000255:Adenosine Triphosphate; D017479:Receptors, Platelet-Derived Growth Factor