Identification of a novel benzyloxy-terminated scaffold as a potent and selective TYK2 inhibitor for anti-inflammatory therapy

  • Eur J Med Chem. 2026 Jan 5:301:118211. doi: 10.1016/j.ejmech.2025.118211.
Yang Tian  1 ,  Yanzhuo Liu  2 ,  Jianyu Liu  2 ,  Jing Luo  1 ,  Jingwen Zhang  1 ,  Xiong Zhang  1 ,  Hengkang He  1 ,  Yixi Xiao  1 ,  Jianhui Zhang  3 ,  Tao Yang  4
Affiliations
  • 1. Department of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, 610014, Sichuan, China; Medical Research Center, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, 610031, Sichuan, China.
  • 2. Medical Research Center, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, 610031, Sichuan, China.
  • 3. Department of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, 610014, Sichuan, China. Electronic address: [email protected].
  • 4. National Chengdu Center for Safety Evaluation of Drugs, West China Hospital of Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 41072266 DOI: 10.1016/j.ejmech.2025.118211
Abstract

In this study, we described three series of N-phenylpyrimidin-2-amine derivatives as selective Tyk2 inhibitors. Systematic exploration of the structure-activity relationship through the introduction of an O-linker and the flexible benzyl substituent based on the reported non-selective JAKs inhibitor yt52 led to the discovery of the optimized derivative compound 29i. Compound 29i showed a potency on Tyk2 with an IC50 value of 18 nM and exhibited more than >70-fold selectivity over JAK1/2/3 isoforms. Kinase panel screening, WB assays, and human peripheral blood mononuclear cell assays further validated the selectivity of compound 29i. Compound 29i demonstrated pharmacokinetic properties with an oral bioavailability of 42.7 %. Moreover, in models of inflammatory disease (allergic rhinitis) and autoimmune disease (alopecia areata), compound 29i demonstrated comparable therapeutic effects to market drugs. Taken together, these findings establish that compound 29i is a selective Tyk2 Inhibitor with compelling potential for clinical development.

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