Identification of 4-aminopyrazolylpyrimidines as potent inhibitors of Trk kinases.
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.
Wang
Tao
T
Department of Cancer Chemistry, AstraZeneca R&D Boston, Waltham, Massachusetts 02451, USA. tao.wang@astrazeneca.com
Lamb
Michelle L
ML
Scott
David A
DA
Wang
Haixia
H
Block
Michael H
MH
Lyne
Paul D
PD
Lee
John W
JW
Davies
Audrey M
AM
Zhang
Hai-Jun
HJ
Zhu
Yanyi
Y
Gu
Fei
F
Han
Yongxin
Y
Wang
Bin
B
Mohr
Peter J
PJ
Kaus
Robert J
RJ
Josey
John A
JA
Hoffmann
Ethan
E
Thress
Ken
K
Macintyre
Terry
T
Wang
Haiyun
H
Omer
Charles A
CA
Yu
Dingwei
D
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
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