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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 |
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| Authors: | Lombardo Louis J Lee Francis Y Chen Ping Norris Derek Barrish Joel C Behnia Kamelia Castaneda Stephen Cornelius Lyndon A M Das Jagabandhu Doweyko Arthur M Fairchild Craig Hunt John T Inigo Ivan Johnston Kathy Kamath Amrita Kan David Klei Herbert Marathe Punit Pang Suhong Peterson Russell Pitt Sidney Schieven Gary L Schmidt Robert J Tokarski John Wen Mei-Li Wityak John Borzilleri Robert M |
| Affiliation: | Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. louis.lombardo@bms.com |
| 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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