2. Academic Validation
  3. Design, synthesis, and pharmacological evaluation of quinazoline derivatives as novel and potent pan-JAK inhibitors

Design, synthesis, and pharmacological evaluation of quinazoline derivatives as novel and potent pan-JAK inhibitors

  • Bioorg Chem. 2023 Nov:140:106765. doi: 10.1016/j.bioorg.2023.106765.
Jinbao Xiang 1,  Yuji Wang 2,  Wanhe Wang 1,  Jianxin Yu 2,  Lianyou Zheng 1,  Yuan Hong 2,  Lingling Shi 1,  Chunling Zhang 1,  Na Chen 2,  Jia Xu 2,  Xuelian Gong 2,  Zhuoqi Zhang 1,  Hongming Cui 1,  Qian Zhou 1,  Dapeng Zhang 1,  Yanjun Liu 2,  Ying Ke 2,  Jingkang Shen 2,  Guangxin Xia 3,  Xu Bai 4
Affiliations

Affiliations

  • 1 The Center for Combinatorial Chemistry and Drug Discovery of Jilin University, The School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, PR China.
  • 2 Central Research Institute, National Key Laboratory of Innovative Immunotherapy, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai 201203, PR China.
  • 3 Central Research Institute, National Key Laboratory of Innovative Immunotherapy, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai 201203, PR China. Electronic address: xiagx@sphchina.com.
  • 4 The Center for Combinatorial Chemistry and Drug Discovery of Jilin University, The School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, PR China. Electronic address: xbai@jlu.edu.cn.
PMID: 37582330 DOI: 10.1016/j.bioorg.2023.106765
Abstract

Janus kinases (JAKs) play a critical role in modulating the function and expression of inflammatory cytokines related to rheumatoid arthritis (RA). Herein, we report the design, synthesis, and structure-activity relationships (SARs) of a series of novel quinazoline derivatives as JAK inhibitors. Among these inhibitors, compound 11n showed high potency against JAKs (JAK1/JAK2/JAK3/Tyk2, IC50 = 0.40, 0.83, 2.10, 1.95 nM), desirable metabolic characters, and excellent pharmacokinetic properties. In collagen-induced arthritis (CIA) models, compound 11n exhibited significant reduction in joint swelling with good safety, which could be served as a potential therapeutic candidate for the treatment of inflammatory diseases.

Keywords

Anti-inflammation; JAK inhibitor; Quinazoline; Rheumatoid arthritis.

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