Novel 2-Aminopyrimidine Carbamates as Potent and Orally Active Inhibitors of Lck: Synthesis, SAR, and in Vivo Antiinflammatory Activity

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• 作者：Matthew W. Martin ; John Newcomb ; Joseph J. Nunes ; David C. McGowan ; David M. Armistead ; Christina Boucher ; John L. Buchanan ; William Buckner ; Lilly Chai ; Daniel Elbaum ; Linda F. Epstein ; Theodore Faus
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：August 10, 2006
• 年：2006
• 卷：49
• 期：16
• 页码：4981 - 4991
• 全文大小：310K
• 年卷期：v.49,no.16(August 10, 2006)
• ISSN：1520-4804

文摘

The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in Tcells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity iscritical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development andactivation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T cell-mediatedautoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe thesynthesis, structure-activity relationships, and pharmacological characterization of 2-aminopyrimidinecarbamates, a new class of compounds with potent and selective inhibition of Lck. The most promisingcompound of this series, 2,6-dimethylphenyl 2-((3,5-bis(methyloxy)-4-((3-(4-methyl-1-piperazinyl)propyl)oxy)phenyl)amino)-4-pyrimidinyl(2,4-bis(methyloxy)phenyl)carbamate (43) exhibits good activity whenevaluated in in vitro assays and in an in vivo model of T cell activation.