title: 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.
abstract: 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.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. louis.lombardo@bms.com
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Lombardo
authors.forename: Francis Y
authors.initials: FY
authors.lastname: Lee
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Derek
authors.initials: D
authors.lastname: Norris
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.forename: Kamelia
authors.initials: K
authors.lastname: Behnia
authors.forename: Stephen
authors.initials: S
authors.lastname: Castaneda
authors.forename: Lyndon A M
authors.initials: LA
authors.lastname: Cornelius
authors.forename: Jagabandhu
authors.initials: J
authors.lastname: Das
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Doweyko
authors.forename: Craig
authors.initials: C
authors.lastname: Fairchild
authors.forename: John T
authors.initials: JT
authors.lastname: Hunt
authors.forename: Ivan
authors.initials: I
authors.lastname: Inigo
authors.forename: Kathy
authors.initials: K
authors.lastname: Johnston
authors.forename: Amrita
authors.initials: A
authors.lastname: Kamath
authors.forename: David
authors.initials: D
authors.lastname: Kan
authors.forename: Herbert
authors.initials: H
authors.lastname: Klei
authors.forename: Punit
authors.initials: P
authors.lastname: Marathe
authors.forename: Suhong
authors.initials: S
authors.lastname: Pang
authors.forename: Russell
authors.initials: R
authors.lastname: Peterson
authors.forename: Sidney
authors.initials: S
authors.lastname: Pitt
authors.forename: Gary L
authors.initials: GL
authors.lastname: Schieven
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schmidt
authors.forename: John
authors.initials: J
authors.lastname: Tokarski
authors.forename: Mei-Li
authors.initials: ML
authors.lastname: Wen
authors.forename: John
authors.initials: J
authors.lastname: Wityak
authors.forename: Robert M
authors.initials: RM
authors.lastname: Borzilleri
mesh_terms: 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
chemical_list: 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