2. Academic Validation
  3. Discovery of triazolo [1,5-a] pyridine derivatives as novel JAK1/2 inhibitors

Discovery of triazolo [1,5-a] pyridine derivatives as novel JAK1/2 inhibitors

  • Bioorg Med Chem Lett. 2020 Jul 15;30(14):127225. doi: 10.1016/j.bmcl.2020.127225.
Kuan Lu 1,  Weibin Wu 2,  Cunlong Zhang 2,  Zijian Liu 3,  Boren Xiao 4,  Zigao Yuan 3,  Anqi Li 4,  Dawei Chen 3,  Xin Zhai 5,  Yuyang Jiang 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China; Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518057, PR China.
  • 2 Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518057, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 3 Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518057, PR China.
  • 4 Department of Chemistry, Tsinghua University, Beijing 100084, PR China.
  • 5 Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China. Electronic address: zhaixin_syphu@126.com.
  • 6 Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China; Joint Key State Laboratory of Tumor Chemogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, PR China. Electronic address: jiangyy@sz.tsinghua.edu.cn.
PMID: 32527540 DOI: 10.1016/j.bmcl.2020.127225
Abstract

Small molecule JAK inhibitors have been demonstrated efficacy in rheumatoid arthritis, inflammatory bowel disease, and psoriasis with the approval of several drugs. Aiming to develop potent JAK1/2 inhibitors, two series of triazolo [1,5-a] pyridine derivatives were designed and synthesized by various strategies. The pharmacological results identified the optimized compounds J-4 and J-6, which exerted high potency against JAK1/2, and selectivity over JAK3 in Enzyme assays. Furthermore, J-4 and J-6 effectively suppressed proliferation of JAK1/2 high-expression BaF3 cells accompanied with acceptable metabolic stability in liver microsomes. Therefore, J-4 and J-6 might serve as promising JAK1/2 inhibitors for further investigation.

Keywords

Anti-inflammatory; Drug design; JAK1/2 inhibitors; Triazolo [1,5-a] pyridine derivatives.

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