Structure-Guided Design of Aminopyrimidine Amides as Potent, Selective Inhibitors of Lymphocyte Specific Kinase: Synthesis, Structure–Activity Relationships, and Inhibition of in Vivo T Cell Ac

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• 作者：Erin F. DiMauro ; John Newcomb ; Joseph J. Nunes ; Jean E. Bemis ; Christina Boucher ; Lilly Chai ; Stuart C. Chaffee ; Holly L. Deak ; Linda F. Epstein ; Ted Faust ; Paul Gallant ; Anu Gore ; Yan Gu ; Brad Henkle
• 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：1681 - 1694
• 全文大小：785K
• 年卷期：v.51,no.6(March 27, 2008)
• ISSN：1520-4804

文摘

The lymphocyte-specific kinase (Lck), a member of the Src family of cytoplasmic tyrosine kinases, is expressed in T cells and natural killer (NK) cells. Genetic evidence, including knockout mice and human mutations, demonstrates that Lck kinase activity is critical for normal T cell development, activation, and signaling. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. With the aid of X-ray structure-based analysis, aminopyrimidine amides 2 and 3 were designed from aminoquinazolines 1, which had previously been demonstrated to exhibit potent inhibition of Lck and T cell proliferation. In this report, we describe the synthesis and structure–activity relationships of a series of novel aminopyrimidine amides 3 possessing improved cellular potency and selectivity profiles relative to their aminoquinazoline predecessors 1. Orally bioavailable compound 13b inhibited the anti-CD3-induced production of interleukin-2 (IL-2) in mice in a dose-dependent manner (ED₅₀ = 9.4 mg/kg).