Structure‐guided design of potent JAK1‐selective inhibitors based on 4‐amino‐7H‐pyrrolo[2,3‐d]pyrimidine with anti‐inflammatory efficacy

• Published in: Archiv der Pharmazie (Weinheim) 2024-04, Vol.357 (4), p.e2300591-n/a
• Main Authors: Zhang, Jiahao, Xing, Shuming, Cui, Jianming, Wei, Xiujian, Cao, Zhi, Shao, Bin, Jiang, Nan, Zhai, Xin
• Format: Article
• Language: English
• Subjects: 4‐amino‐7H‐pyrrolo[2,3‐d]pyrimidine; anti‐inflammatory; JAK1‐selective inhibitor; liver fibrosis; RAW264.7 macrophages
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.202300591

In a continuous effort to develop Janus kinase 1 (JAK1)‐selective inhibitors, a novel series of 4‐amino‐7H‐pyrrolo[2,3‐d]pyrimidine derivatives bearing the piperidinyl fragment were designed and synthesized according to a combination strategy. Through enzymatic assessments, the superior compound 12a with an IC50 value of 12.6 nM against JAK1 was identified and a 10.7‐fold selectivity index over JAK2 was achieved. It was indicated that 12a displayed considerable effect in inhibiting the pro‐inflammatory NO generated from lipopolysaccharide (LPS)‐induced RAW264.7 macrophages, while on normal RAW264.7 cells, 12a exerted a weak cytotoxicity effect (IC50 = 143.3 μM). Furthermore, H&E stain assay demonstrated the conspicuous capacity of 12a to suppress CCl4‐induced hepatic fibrosis levels in a dose‐dependent manner in vivo. The binding model of 12a ideally reflects the excellent activity of JAK1 over the homologous kinase JAK2. Overall, 12a, a JAK1‐selective inhibitor, exhibited potential for liver fibrosis and inflammatory diseases. A combination strategy based on JA 4 and abrocitinib, in which the pyrazole ring of JA 4 is replaced with a nitrogen atom, identified compound 12a as an optimal Janus kinase 1‐selective inhibitor (IC50 = 12.6 nM, selectivity index = 10.7). Further biological evaluation confirmed that 12a was a potential candidate for treating inflammation and liver fibrosis.