title: Identification and optimization of N3,N6-diaryl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamines as a novel class of ACK1 inhibitors.
abstract: 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.
authors.affiliation: Department of Chemistry, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. dkopecky@amgen.com
authors.forename: David J
authors.initials: DJ
authors.lastname: Kopecky
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Hao
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Jiasheng
authors.initials: J
authors.lastname: Fu
authors.forename: XianYun
authors.initials: X
authors.lastname: Jiao
authors.forename: Juan C
authors.initials: JC
authors.lastname: Jaen
authors.forename: Mario G
authors.initials: MG
authors.lastname: Cardozo
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.forename: Zhulun
authors.initials: Z
authors.lastname: Wang
authors.forename: Nigel P C
authors.initials: NP
authors.lastname: Walker
authors.forename: Holger
authors.initials: H
authors.lastname: Wesche
authors.forename: Shyun
authors.initials: S
authors.lastname: Li
authors.forename: Ellyn
authors.initials: E
authors.lastname: Farrelly
authors.forename: Shou-Hua
authors.initials: SH
authors.lastname: Xiao
authors.forename: Frank
authors.initials: F
authors.lastname: Kayser
mesh_terms: 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
chemical_list: D003959:Diamines; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C403262:TNK2 protein, human