Design and synthesis of 1,5-diarylbenzimidazoles as inhibitors of the VEGF-receptor KDR.
1,5-Diarylbenzimidazoles have been identified as potent inhibitors of KDR kinase activity. The series was developed with a goal of finding compounds with optimal drug-like properties. This communication describes structural modifications in the series that enhance solubility, lower protein binding, and provide compounds with excellent potency and pharmacokinetic profiles.
Bilodeau
Mark T
MT
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA. mark_bilodeau@merck.com
Cunningham
April M
AM
Koester
Timothy J
TJ
Ciecko
Patrice A
PA
Coll
Kathleen E
KE
Huckle
William R
WR
Hungate
Randall W
RW
Kendall
Richard L
RL
McFall
Rosemary C
RC
Mao
Xianzhi
X
Rutledge
Ruth Z
RZ
Thomas
Kenneth A
KA
D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004285:Dogs; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents; D008968:Molecular Conformation; D051381:Rats; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D040301:Vascular Endothelial Growth Factor Receptor-2