贾纳斯激酶
类风湿性关节炎
托法替尼
药理学
体内
银屑病
化学
银屑病性关节炎
效力
甲氨蝶呤
关节炎
炎症性肠病
医学
激酶
体外
免疫学
内科学
疾病
生物化学
生物
生物技术
作者
Jigar Desai,Bhaumin Patel,Archana Gite,Nandini Panchal,Sanjay Gite,Anil Argade,Jeevan Kumar,Mukesh Chourasia,Debdutta Bandyopadhyay,Krishnarup Ghoshdastidar,Hoshang Patel,Abhijit Chatterjee,Jogeshwar Mahapatra,Manoranjan Sharma,Poonam Giri,Sanjay Kumar,Mukul Jain,Rajiv Sharma,Ranjit C. Desai
标识
DOI:10.1016/j.bmcl.2022.128728
摘要
Dysregulated JAK-STAT signaling has been proven to be involved in several immune-mediated diseases. Several janus kinase (JAK) inhibitors have been approved for the treatment of various inflammatory and autoimmune diseases such as rheumatoid arthritis (RA), plaque psoriasis, psoriatic arthritis, inflammatory bowel disease (IBD). Here, we report the design, optimisation, synthesis and biological evaluation of momelotinib analogues (a pyrimidine based JAK inhibitor), to get pan-JAK inhibitors. Systematic structure activity relationship studies led to the discovery of compound 32, which potently inhibited JAK1, JAK2 and JAK3. The in vivo investigation indicated that compound 32 possessed favourable pharmacokinetic properties and displayed superior anti-inflammatory efficacy than momelotinib 1. Accordingly, compound 32 was advanced into preclinical development.
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