Identification and optimization of N3,N6-diaryl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamines as a novel class of ACK1 inhibitors.
A new series of pyrazolo[3,4-d]pyrimidine-3,6-diamines was designed and synthesized as potent and selective inhibitors of the nonreceptor tyrosine kinase, ACK1. These compounds arose from efforts to rigidify an earlier series of N-aryl pyrimidine-5-carboxamides. The synthesis and structure-activity relationships of this new series of inhibitors are reported. The most promising compounds were also profiled for their pharmacokinetic properties.
Kopecky
David J
DJ
Department of Chemistry, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. dkopecky@amgen.com
Hao
Xiaolin
X
Chen
Yi
Y
Fu
Jiasheng
J
Jiao
XianYun
X
Jaen
Juan C
JC
Cardozo
Mario G
MG
Liu
Jinsong
J
Wang
Zhulun
Z
Walker
Nigel P C
NP
Wesche
Holger
H
Li
Shyun
S
Farrelly
Ellyn
E
Xiao
Shou-Hua
SH
Kayser
Frank
F
D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D003959:Diamines / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008297:Male; D008956:Models, Chemical; D008968:Molecular Conformation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011720:Pyrazoles / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D003959:Diamines; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C403262:TNK2 protein, human