Structure-Based Design of Novel 2-Amino-6-phenyl-pyrimido[5′,4′:5,6]pyrimido[1,2-a]benzimidazol-5(6H)-ones as Potent and Orally Active Inhibitors of Lymphocyte Specific Kin

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• 作者：Matthew W. Martin ; John Newcomb ; Joseph J. Nunes ; Christina Boucher ; Lilly Chai ; Linda F. Epstein ; Theodore Faust ; Sylvia Flores ; Paul Gallant ; Anu Gore ; Yan Gu ; Faye Hsieh ; Xin Huang ; Joseph L. Kim
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：March 27, 2008
• 年：2008
• 卷：51
• 期：6
• 页码：1637 - 1648
• 全文大小：1064K
• 年卷期：v.51,no.6(March 27, 2008)
• ISSN：1520-4804

文摘

Lck, or lymphocyte specific kinase, is a cytoplasmic tyrosine kinase of the Src family expressed in T-cells and NK cells. Genetic evidence from knockout mice and human mutations demonstrates that Lck kinase activity is critical for T-cell receptor-mediated signaling, leading to normal T-cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T-cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the structure-guided design, synthesis, structure–activity relationships, and pharmacological characterization of 2-amino-6-phenylpyrimido[5′,4′:5,6]pyrimido[1,2-a]benzimidazol-5(6H)-ones, a new class of compounds that are potent inhibitors of Lck. The most promising compound of this series, 6-(2,6-dimethylphenyl)-2-((4-(4-methyl-1-piperazinyl)phenyl)amino)pyrimido[5′,4′:5,6]pyrimido-[1,2-a]benzimidazol-5(6H)-one (25), exhibits potent inhibition of Lck kinase activity. This activity translates into inhibition of in vitro cell-based assays and in vivo models of T-cell activation and arthritis, respectively.