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

  • J Med Chem. 2004 Dec 30;47(27):6658-61. doi: 10.1021/jm049486a.
Louis J Lombardo  1 ,  Francis Y Lee ,  Ping Chen ,  Derek Norris ,  Joel C Barrish ,  Kamelia Behnia ,  Stephen Castaneda ,  Lyndon A M Cornelius ,  Jagabandhu Das ,  Arthur M Doweyko ,  Craig Fairchild ,  John T Hunt ,  Ivan Inigo ,  Kathy Johnston ,  Amrita Kamath ,  David Kan ,  Herbert Klei ,  Punit Marathe ,  Suhong Pang ,  Russell Peterson ,  Sidney Pitt ,  Gary L Schieven ,  Robert J Schmidt ,  John Tokarski ,  Mei-Li Wen ,  John Wityak ,  Robert M Borzilleri
Affiliations
  • 1. Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. [email protected]
PMID: 15615512 DOI: 10.1021/jm049486a
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.

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