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(6 H)-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(6 H)-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.

中文翻译：

---

基于结构的新型2-氨基-6-苯基-嘧啶[5'，4'：5,6]嘧啶[1,2-a]苯并咪唑-5（6H）-酮作为有效和口服活性的淋巴细胞抑制剂的设计特异性激酶（Lck）：合成，SAR和体内抗炎活性。

Lck或淋巴细胞特异性激酶是在T细胞和NK细胞中表达的Src家族的胞质酪氨酸激酶。基因敲除小鼠和人类突变的遗传证据表明，Lck激酶活性对于T细胞受体介导的信号传导至关重要，从而导致正常的T细胞发育和激活。预期Lck的小分子抑制剂可用于治疗T细胞介导的自身免疫和炎性疾病和/或器官移植排斥。在本文中，我们描述了2-氨基-6-苯基嘧啶[5'，4'：5,6]嘧啶[1,2-a]苯并咪唑的结构指导设计，合成，构效关系和药理学表征-5（6 H）-one，一类新型的Lck抑制剂。该系列中最有前途的化合物6-（2，6-二甲基苯基）-2-（（（4-（4-甲基-1-哌嗪基）苯基）氨基）嘧啶基[5'，4'：5,6]嘧啶基-[1,2-a]苯并咪唑-5（6 H）一（25）显示出对Lck激酶活性的有效抑制。该活性分别转化为对基于T细胞活化和关节炎的体外基于细胞的测定和体内模型的抑制。