Discovery and evaluation of 3-(5-thien-3-ylpyridin-3-yl)-1H-indoles as a novel class of KDR kinase inhibitors.
We have discovered 3-(5-thien-3-ylpyridin-3-yl)-1H-indoles as potent inhibitors of KDR kinase activity. This communication details the evolution of this novel class from a potent screening lead of vastly different structure with an emphasis on structural modifications that retained activity and provided improvements in key physical properties. The synthesis and in-depth evaluation of these inhibitors are described.
Fraley
Mark E
ME
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. mark_fraley@merck.com
Arrington
Kenneth L
KL
Hambaugh
Scott R
SR
Hoffman
William F
WF
Cunningham
April M
AM
Young
Mary Beth
MB
Hungate
Randall W
RW
Tebben
Andrew J
AJ
Rutledge
Ruth Z
RZ
Kendall
Richard L
RL
Huckle
William R
WR
McFall
Rosemary C
RC
Coll
Kathleen E
KE
Thomas
Kenneth A
KA
D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D006207:Half-Life; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D051381:Rats; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D020533:Angiogenesis Inhibitors; D007211:Indoles; D040301:Vascular Endothelial Growth Factor Receptor-2