2-Aminothiazole as a Novel Kinase Inhibitor Template. Structure-Activity Relationship Studies toward the Discovery of N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-me
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- 作者：Jagabandhu Das ; Ping Chen ; Derek Norris ; Ramesh Padmanabha ; James Lin ; Robert V. Moquin ; Zhongqi Shen ; Lynda S. Cook ; Arthur M. Doweyko ; Sidney Pitt ; Suhong Pang ; Ding Ren Shen ; Qiong Fang ; Henry F. d
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：November 16, 2006
- 年：2006
- 卷：49
- 期：23
- 页码：6819 - 6832
- 全文大小：396K
- 年卷期：v.49,no.23(November 16, 2006)
- ISSN：1520-4804
文摘
2-Aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening ofour internal compound collection. Optimization through successive structure-activity relationship iterationsidentified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolarpotencies in biochemical and cellular assays. Molecular modeling was used to construct a putative bindingmodel for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactionsproposed by this model was in agreement with the subsequent, published crystal structure of 2 bound tostructurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m ininhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED50 ~ 5 mg/kg) and in reducing TNFlevels in an acute murine model of inflammation (90% inhibition in LPS-induced TNF
production whendosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstratedin a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenousleukemia.
production whendosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstratedin a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenousleukemia.