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