Replacement of pyrazol-3-yl amine hinge binder with thiazol-2-yl amine: Discovery of potent and selective JAK2 inhibitors.
Thiazol-2-yl amine was identified as an isosteric replacement for pyrazol-3-yl amine during our efforts to identify potent and selective JAK2 inhibitors. The rationale, synthesis and biological evaluation of several analogs is reported, along with the in vivo evaluation of the lead compounds.
Department of Cancer Chemistry, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. Stephanos.Ioannidis@astrazeneca.com
Stephanos
S
Ioannidis
Michelle L
ML
Lamb
Lynsie
L
Almeida
Huiping
H
Guan
Bo
B
Peng
Geraldine
G
Bebernitz
Kirsten
K
Bell
Marat
M
Alimzhanov
Michael
M
Zinda
D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D055808:Drug Discovery; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008861:Microsomes / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry*; D051381:Rats; D013844:Thiazoles / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
D000588:Amines; D000970:Antineoplastic Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D013844:Thiazoles; D053614:Janus Kinase 2