2. Academic Validation
  3. Design, synthesis and evaluation of C-5 substituted pyrrolopyridine derivatives as potent Janus Kinase 1 inhibitors with excellent selectivity

Design, synthesis and evaluation of C-5 substituted pyrrolopyridine derivatives as potent Janus Kinase 1 inhibitors with excellent selectivity

  • Eur J Med Chem. 2024 Mar 5:267:116210. doi: 10.1016/j.ejmech.2024.116210.
Limei Chen 1,  Yahua Tang 2,  Jia-Jia Lang 3,  Yuqing Lin 1,  Zhixin Yu 1,  Xinhao Li 1,  Xing Zheng 4,  Pengbing Mi 5,  You Lv 6,  Ying-Wu Lin 7
Affiliations

Affiliations

  • 1 Department of Pharmacy, Hengyang Medicinal School, University of South China, Hengyang, Hunan, 421001, China.
  • 2 The Affiliated Nanhua Hospital, Department of Pharmacy, Institute of Clinical Pharmacy, Hengyang Medical School, University of South China, Hunan, 421001, China.
  • 3 School of Chemistry and Chemical Engineering, University of South China, Hengyang, Hunan, 421001, China; Key Lab of Protein Structure and Function of Universities in Hunan Province, University of South China, Hengyang, Hunan, 421001, China.
  • 4 Department of Pharmacy, Hengyang Medicinal School, University of South China, Hengyang, Hunan, 421001, China; Department of Pharmacy, Hunan Vocational College of Science and Technology, Changsha, Hunan, 410004, China.
  • 5 Department of Pharmacy, Hengyang Medicinal School, University of South China, Hengyang, Hunan, 421001, China; Key Lab of Protein Structure and Function of Universities in Hunan Province, University of South China, Hengyang, Hunan, 421001, China. Electronic address: geyynb@foxmail.com.
  • 6 College of Bioresources Chemical and Materials Engineering, Shaanxi University of Science & Technology, Xi'an, Shaanxi, 710021, China; Xi'an Amazinggene Co., Ltd, Xi'an, Shaanxi, 710026, China. Electronic address: lvyou@sust.edu.cn.
  • 7 School of Chemistry and Chemical Engineering, University of South China, Hengyang, Hunan, 421001, China; Key Lab of Protein Structure and Function of Universities in Hunan Province, University of South China, Hengyang, Hunan, 421001, China. Electronic address: ywlin@usc.edu.cn.
PMID: 38359535 DOI: 10.1016/j.ejmech.2024.116210
Abstract

The development of highly selective Janus Kinase 1 (JAK1) inhibitors is crucial for improving efficacy and minimizing adverse effects in the clinical treatment of autoimmune diseases. In a prior study, we designed a series of C-5 4-pyrazol substituted pyrrolopyridine derivatives that demonstrated significant potency against JAK1, with a 10 ∼ 20-fold selectivity over Janus Kinase 2 (JAK2). Building on this foundation, we adopted orthogonal strategy by modifying the C-5 position with 3-pyrazol/4-pyrazol/3-pyrrol groups and tail with substituted benzyl groups on the pyrrolopyridine head to enhance both potency and selectivity. In this endeavor, we have identified several compounds that exhibit excellent potency and selectivity for JAK1. Notably, compounds 12b and 12e, which combined 4-pyrazol group at C-5 site and meta-substituted benzyl tails, displayed IC50 value with 2.4/2.2 nM and high 352-/253-fold selectivity for JAK1 over JAK2 in Enzyme assays. Additionally, both compounds showed good JAK1-selective in Ba/F3-TEL-JAK1/2 cell-based assays. These findings MARK a substantial improvement, as these compounds are 10-fold more potent and over 10-fold more selective than the best compound identified in our previous study. The noteworthy potency and selectivity properties of compounds 12b and 12e suggest their potential utility in furthering the development of drugs for autoimmune diseases.

Keywords

Autoimmune diseases; JAK-STAT pathway; JAK1-Selective inhibitor; Orthogonal strategy; Pyrrolopyridine skeleton.

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