Discovery of Aminoquinazolines as Potent, Orally Bioavailable Inhibitors of Lck: Synthesis, SAR, and in Vivo Anti-Inflammatory Activity
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- 作者：Erin F. DiMauro ; John Newcomb ; Joseph J. Nunes ; Jean E. Bemis ; Christina Boucher ; John L. Buchanan ; William H. Buckner ; Victor J. Cee ; Lilly Chai ; Holly L. Deak ; Linda F. Epstein ; Ted Faust ; Paul Gal
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：September 21, 2006
- 年：2006
- 卷：49
- 期：19
- 页码：5671 - 5686
- 全文大小：406K
- 年卷期：v.49,no.19(September 21, 2006)
- ISSN：1520-4804
文摘
The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in Tcells and natural killer (NK) cells. Genetic evidence in both mice and humans demonstrates that Lck kinaseactivity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T celldevelopment and activation. Selective inhibition of Lck is expected to offer a new therapy for the treatmentof T-cell-mediated autoimmune and inflammatory disease. Screening of our kinase-preferred collectionidentified aminoquinazoline 1 as a potent, nonselective inhibitor of Lck and T cell proliferation. In thisreport, we describe the synthesis and structure-activity relationships of a series of novel aminoquinazolinespossessing in vitro mechanism-based potency. Optimized, orally bioavailable compounds 32 and 47 exhibitanti-inflammatory activity (ED50 of 22 and 11 mg/kg, respectively) in the anti-CD3-induced production ofinterleukin-2 (IL-2) in mice.