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Discovery of <i>N</i>-(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

Journal of Medicinal Chemistry · 2004 · Vol. 47(27) · pp. 6658–6661

Louis J. Lombardo✉(Bristol-Myers Squibb (United States))Francis Y. Lee(Bristol-Myers Squibb (United States))Ping Chen(Bristol-Myers Squibb (United States))Derek Norris(Bristol-Myers Squibb (United States))Joel C. Barrish(Bristol-Myers Squibb (United States))Kamelia Behnia(Bristol-Myers Squibb (United States))Stephen Castaneda(Bristol-Myers Squibb (United States))Lyndon A. M. Cornelius(Bristol-Myers Squibb (United States))Jagabandhu Das(Bristol-Myers Squibb (United States))Arthur M. Doweyko(Bristol-Myers Squibb (United States))Craig Fairchild(Bristol-Myers Squibb (United States))John T. Hunt(Bristol-Myers Squibb (United States))Ivan Inigo(Bristol-Myers Squibb (United States))Kathy Johnston(Bristol-Myers Squibb (United States))Amrita V. Kamath(Bristol-Myers Squibb (United States))David Kan(Bristol-Myers Squibb (United States))Herbert E. Klei(Bristol-Myers Squibb (United States))Punit Marathe(Bristol-Myers Squibb (United States))Suhong Pang(Bristol-Myers Squibb (United States))Russell W. Peterson(Bristol-Myers Squibb (United States))Sidney Pitt(Bristol-Myers Squibb (United States))Gary L. Schieven(Bristol-Myers Squibb (United States))Robert J. Schmidt(Bristol-Myers Squibb (United States))John S. Tokarski(Bristol-Myers Squibb (United States))Mei-Li Wen(Bristol-Myers Squibb (United States))John Wityak(Bristol-Myers Squibb (United States))R. M. Borzilleri(Bristol-Myers Squibb (United States))

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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.

Chronic Myeloid Leukemia Treatments Quinazolinone synthesis and applications Fungal Plant Pathogen ControlChemistryCarboxamideChronic myelogenous leukemiaProto-oncogene tyrosine-protein kinase SrcPharmacologyThiazoleIn vivoABLEx vivoK562 cells

MeSH terms

DasatinibAdenosine TriphosphateAnimalsAntineoplastic AgentsEnzyme InhibitorsHumansPyrimidinesThiazolesProto-Oncogene Proteins c-ablRats, Sprague-Dawleysrc-Family KinasesK562 CellsMiceRats

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