Potent 2-[(pyrimidin-4-yl)amine}-1,3-thiazole-5-carbonitrile-based inhibitors of VEGFR-2 (KDR) kinase.
Pyrimidino-thiazolyl carbonitriles were prepared that are potent VEGFR-2 (KDR) kinase inhibitors. The modification of lead structures resulted in 3m which exhibited the best overall profile in KDR inhibitory activity, iv/po pharmacokinetics, and reduced hERG affinity.
Sisko
John T
JT
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA. jack_sisko@merck.com
Tucker
Thomas J
TJ
Bilodeau
Mark T
MT
Buser
Carolyn A
CA
Ciecko
Patrice A
PA
Coll
Kathleen E
KE
Fernandes
Christine
C
Gibbs
Jackson B
JB
Koester
Timothy J
TJ
Kohl
Nancy
N
Lynch
Joseph J
JJ
Mao
Xianzhi
X
McLoughlin
Debra
D
Miller-Stein
Cynthia M
CM
Rodman
Leonard D
LD
Rickert
Keith W
KW
Sepp-Lorenzino
Laura
L
Shipman
Jennifer M
JM
Thomas
Kenneth A
KA
Wong
Bradley K
BK
Hartman
George D
GD
D000818:Animals; D004285:Dogs; D008253:Macaca mulatta; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D040301:Vascular Endothelial Growth Factor Receptor-2