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
  • 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: [email protected].
  • 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: [email protected].
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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