Discovery of potent anti-inflammatory 4-(4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl) pyrimidin-2-amines for use as Janus kinase inhibitors.,Bioorganic & Medicinal Chemistry

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Discovery of potent anti-inflammatory 4-(4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl) pyrimidin-2-amines for use as Janus kinase inhibitors.
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2019-03-25 , DOI: 10.1016/j.bmc.2019.03.048
Yazhou Wang ₁ , Wei Huang ₁ , Minhang Xin ₂ , Pan Chen ₃ , Li Gui ₃ , Xinxin Zhao ₃ , Xinrong Zhu ₄ , Hongpeng Luo ₄ , Xin Cong ₄ , Jia Wang ₄ , Fei Liu ₃

Affiliation

The Janus kinase (JAK) family of tyrosine kinases has been proven to provide targeted immune modulation. Orally available JAK inhibitors have been used for the treatment of immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA). Here, we report the design, synthesis and biological evaluation of 4-(4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl) pyrimidin-2-amino derivatives as JAK inhibitors. Systematic structure-activity relationship studies led to the discovery of compound 7j, which strongly inhibited the four isoforms of JAK kinases. Molecular modeling rationalized the importance of cyanoacetyl and phenylmorpholine moieties. The in vivo investigation indicated that compound 7j possessed favorable pharmacokinetic properties and displayed slightly better anti-inflammatory efficacy than tofacitinib at the same dosage. Accordingly, compound 7j was advanced into preclinical development.

中文翻译：

发现有效的抗炎性4-（4,5,6,7-四氢呋喃[3,2-c]吡啶-2-基）嘧啶-2-胺用作Janus激酶抑制剂。

Janus激酶（JAK）酪氨酸激酶家族已被证明可以提供有针对性的免疫调节。口服可获得的JAK抑制剂已经用于治疗免疫介导的炎性疾病，例如类风湿性关节炎（RA）。在这里，我们报告作为JAK抑制剂的4-（4,5,6,7-四氢呋喃[3,2-c]吡啶-2-基）嘧啶-2-氨基衍生物的设计，合成和生物学评估。系统的结构-活性关系研究导致发现化合物7j，该化合物强烈抑制JAK激酶的四种同工型。分子建模使氰基乙酰基和苯基吗啉部分的重要性合理化。体内研究表明，在相同剂量下，化合物7j具有比tofacitinib更好的药代动力学特性，并且显示出比tofacitinib更好的抗炎功效。因此，

更新日期：2019-03-25

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