title: Identification of 4-aminopyrazolylpyrimidines as potent inhibitors of Trk kinases.
abstract: The design, synthesis and biological evaluation of a series of 4-aminopyrazolylpyrimidines as potent Trk kinase inhibitors is reported. High-throughput screening identified a promising hit in the 4-aminopyrazolylpyrimidine chemotype. Initial optimization of the series led to more potent Trk inhibitors. Further optimization using two strategies resulted in significant improvement of physical properties and led to the discovery of 10z (AZ-23), a potent, orally bioavailable Trk A/B inhibitor. The compound offers the potential to test the hypothesis that modulation of Trk activity will be of benefit in the treatment of cancer and other indications in vivo.
authors.affiliation: Department of Cancer Chemistry, AstraZeneca R&D Boston, Waltham, Massachusetts 02451, USA. tao.wang@astrazeneca.com
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Lamb
authors.forename: David A
authors.initials: DA
authors.lastname: Scott
authors.forename: Haixia
authors.initials: H
authors.lastname: Wang
authors.forename: Michael H
authors.initials: MH
authors.lastname: Block
authors.forename: Paul D
authors.initials: PD
authors.lastname: Lyne
authors.forename: John W
authors.initials: JW
authors.lastname: Lee
authors.forename: Audrey M
authors.initials: AM
authors.lastname: Davies
authors.forename: Hai-Jun
authors.initials: HJ
authors.lastname: Zhang
authors.forename: Yanyi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Fei
authors.initials: F
authors.lastname: Gu
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Han
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohr
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kaus
authors.forename: John A
authors.initials: JA
authors.lastname: Josey
authors.forename: Ethan
authors.initials: E
authors.lastname: Hoffmann
authors.forename: Ken
authors.initials: K
authors.lastname: Thress
authors.forename: Terry
authors.initials: T
authors.lastname: Macintyre
authors.forename: Haiyun
authors.initials: H
authors.lastname: Wang
authors.forename: Charles A
authors.initials: CA
authors.lastname: Omer
authors.forename: Dingwei
authors.initials: D
authors.lastname: Yu
mesh_terms: D000588:Amines / Q000737:chemistry*; D000818:Animals; D002460:Cell Line; D006801:Humans; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020917:Receptor, trkA / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C544309:5-chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; D000588:Amines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D020917:Receptor, trkA