2-Aminoimidazoles inhibitors of TGF-beta receptor 1.
The 4-(5-fluoro-6-methyl-pyridin-2-yl)-5-quinoxalin-6-yl-1H-imidazol-2-ylamine 3 is a potent and selective inhibitor of TGF-betaR1. Substitution of the amino group of 3 typically led to a slight decrease in the affinity for the receptor and in TGF-beta-inducted PAI-luciferase reporter activity. However, 2-acetamidoimidazoles were identified as attractive candidates for further optimization as a result of their significant activity combined to their superior pharmacokinetic profile.
Bonafoux
Dominique
D
Abbot Laboratories, 381 Plantation Street, Worcester, MA 01605-2323, USA. dominique.bonafoux@abbott.com
Chuaqui
Claudio
C
Boriack-Sjodin
P Ann
PA
Fitch
Chris
C
Hankins
Gretchen
G
Josiah
Serene
S
Black
Cheryl
C
Hetu
Gregg
G
Ling
Leona
L
Lee
Wen-Cherng
WC
D000818:Animals; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D008968:Molecular Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
D007093:Imidazoles; D018125:Receptors, Transforming Growth Factor beta; C014973:2-aminoimidazole; D008156:Luciferases