Department of Medicinal Chemistry, Zydus Research Centre, Sarkhej-Bavla, N.H. 8A Moraiya, Ahmedabad 382210, India.
Department of Medicinal Chemistry, Zydus Research Centre, Sarkhej-Bavla, N.H. 8A Moraiya, Ahmedabad 382210, India; Department of Chemistry, Faculty of Science, M.S. University of Baroda, Vadodara 390002, India.
Bioorg Chem. 2020 Jun;99:103851. doi: 10.1016/j.bioorg.2020.103851. Epub 2020 Apr 18.
Selective inhibition of janus kinase (JAK) has been identified as an important strategy for the treatment of autoimmune disorders. Optimization at the C2 and C4-positions of pyrimidine ring of Cerdulatinib led to the discovery of a potent and orally bioavailable 2,4-diaminopyrimidine-5-carboxamide based JAK3 selective inhibitor (11i). A cellular selectivity study further confirmed that 11i preferentially inhibits JAK3 over JAK1, in JAK/STAT signaling pathway. Compound 11i showed good anti-arthritic activity, which could be correlated with its improved oral bioavailability. In the repeat dose acute toxicity study, 11i showed no adverse changes related to gross pathology and clinical signs, indicating that the new class JAK3 selective inhibitor could be viable therapeutic option for the treatment of rheumatoid arthritis.
选择性抑制 Janus 激酶（JAK）已被确定为治疗自身免疫性疾病的重要策略。对 Cerdulatinib 嘧啶环的 C2 和 C4 位进行优化，导致发现了一种有效的、可口服生物利用的基于 2,4-二氨基嘧啶-5-甲酰胺的 JAK3 选择性抑制剂（11i）。细胞选择性研究进一步证实，11i 在 JAK/STAT 信号通路中优先抑制 JAK3 而非 JAK1。化合物 11i 表现出良好的抗关节炎活性，这与其改善的口服生物利用度有关。在重复剂量急性毒性研究中，11i 未显示与大体病理学和临床症状相关的不良反应变化，表明新型 JAK3 选择性抑制剂可能是治疗类风湿关节炎的可行治疗选择。
