title: 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.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, West Point, Pennsylvania 19486, USA. mark_bilodeau@merck.com
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bilodeau
authors.forename: Adrienne E
authors.initials: AE
authors.lastname: Balitza
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Koester
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Manley
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Rodman
authors.forename: Carolyn
authors.initials: C
authors.lastname: Buser-Doepner
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Coll
authors.forename: Christine
authors.initials: C
authors.lastname: Fernandes
authors.forename: Jackson B
authors.initials: JB
authors.lastname: Gibbs
authors.forename: David C
authors.initials: DC
authors.lastname: Heimbrook
authors.forename: William R
authors.initials: WR
authors.lastname: Huckle
authors.forename: Nancy
authors.initials: N
authors.lastname: Kohl
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Mao
authors.forename: Rosemary C
authors.initials: RC
authors.lastname: McFall
authors.forename: Debra
authors.initials: D
authors.lastname: McLoughlin
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Miller-Stein
authors.forename: Keith W
authors.initials: KW
authors.lastname: Rickert
authors.forename: Laura
authors.initials: L
authors.lastname: Sepp-Lorenzino
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Shipman
authors.forename: Raju
authors.initials: R
authors.lastname: Subramanian
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Thomas
authors.forename: Bradley K
authors.initials: BK
authors.lastname: Wong
authors.forename: Sean
authors.initials: S
authors.lastname: Yu
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
mesh_terms: 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
chemical_list: 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