Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.

中文翻译：

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鉴定ñ - {顺式-3- [甲基（7 ħ吡咯并[2,3- d ]嘧啶-4-基）氨基]环丁基}丙烷-1-磺酰胺（PF-04965842）：选择性JAK1临床用于候选自身免疫性疾病的治疗

Janus激酶（JAKs）是细胞内酪氨酸激酶，可介导参与调节免疫力，炎症和造血作用的多种细胞因子和生长因子的信号传导。由于JAK1与JAK2，JAK3和TYK2配对，因此JAK1选择性抑制剂有望抑制许多参与炎症和免疫功能的细胞因子，同时避免抑制JAK2同型二聚体调节促红细胞生成素和血小板生成素的信号传导。我们的工作始于tofacitinib，一种经批准可用于治疗类风湿关节炎的口服JAK抑制剂。通过修饰托法替尼中的3-氨基哌啶连接基，我们在人类全血测定中发现了具有纳摩尔浓度效价的高选择性JAK1抑制剂。通过X射线晶体学分析表明的结构修饰，实现了JAK1效能和选择性的提高。在大鼠佐剂诱导的关节炎（rAIA）模型中证明疗效后，PF-04965842（25）被提名为治疗JAK1介导的自身免疫性疾病的临床候选药物。