Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays.
A series of substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)thiazole-5-carboxamides was identified as potent Src/Abl kinase inhibitors with excellent antiproliferative activity against hematological and solid tumor cell lines. Compound 13 was orally active in a K562 xenograft model of chronic myelogenous leukemia (CML), demonstrating complete tumor regressions and low toxicity at multiple dose levels. On the basis of its robust in vivo activity and favorable pharmacokinetic profile, 13 was selected for additional characterization for oncology indications.
Lombardo
Louis J
LJ
Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. louis.lombardo@bms.com
Lee
Francis Y
FY
Chen
Ping
P
Norris
Derek
D
Barrish
Joel C
JC
Behnia
Kamelia
K
Castaneda
Stephen
S
Cornelius
Lyndon A M
LA
Das
Jagabandhu
J
Doweyko
Arthur M
AM
Fairchild
Craig
C
Hunt
John T
JT
Inigo
Ivan
I
Johnston
Kathy
K
Kamath
Amrita
A
Kan
David
D
Klei
Herbert
H
Marathe
Punit
P
Pang
Suhong
S
Peterson
Russell
R
Pitt
Sidney
S
Schieven
Gary L
GL
Schmidt
Robert J
RJ
Tokarski
John
J
Wen
Mei-Li
ML
Wityak
John
J
Borzilleri
Robert M
RM
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000069439:Dasatinib; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020014:K562 Cells; D051379:Mice; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000255:Adenosine Triphosphate; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases; D000069439:Dasatinib