Potent N-(1,3-thiazol-2-yl)pyridin-2-amine vascular endothelial growth factor receptor tyrosine kinase inhibitors with excellent pharmacokinetics and low affinity for the hERG ion channel.
A series of N-(1,3-thiazol-2-yl)pyridin-2-amine KDR kinase inhibitors have been developed that possess optimal properties. Compounds have been discovered that exhibit excellent in vivo potency. The particular challenges of overcoming hERG binding activity and QTc increases in vivo in addition to achieving good pharmacokinetics have been acomplished by discovering a unique class of amine substituents. These compounds have a favorable kinase selectivity profile that can be accentuated with appropriate substitution.
Bilodeau
Mark T
MT
Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, West Point, Pennsylvania 19486, USA. mark_bilodeau@merck.com
Balitza
Adrienne E
AE
Koester
Timothy J
TJ
Manley
Peter J
PJ
Rodman
Leonard D
LD
Buser-Doepner
Carolyn
C
Coll
Kathleen E
KE
Fernandes
Christine
C
Gibbs
Jackson B
JB
Heimbrook
David C
DC
Huckle
William R
WR
Kohl
Nancy
N
Lynch
Joseph J
JJ
Mao
Xianzhi
X
McFall
Rosemary C
RC
McLoughlin
Debra
D
Miller-Stein
Cynthia M
CM
Rickert
Keith W
KW
Sepp-Lorenzino
Laura
L
Shipman
Jennifer M
JM
Subramanian
Raju
R
Thomas
Kenneth A
KA
Wong
Bradley K
BK
Yu
Sean
S
Hartman
George D
GD
D000284:Administration, Oral; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D004285:Dogs; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels; D066298:In Vitro Techniques; D008168:Lung / Q000201:enzymology; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010766:Phosphorylation; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
C494724:4-(2-(5-cyanothiazol-2-ylamino)pyridin-4-ylmethyl)piperazine-1-carboxylic acid methylamide; D000631:Aminopyridines; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; D013844:Thiazoles; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2