2. Academic Validation
  3. Discovery of C-5 Pyrazole-Substituted Pyrrolopyridine Derivatives as Potent and Selective Inhibitors for Janus Kinase 1

Discovery of C-5 Pyrazole-Substituted Pyrrolopyridine Derivatives as Potent and Selective Inhibitors for Janus Kinase 1

  • J Med Chem. 2023 May 10. doi: 10.1021/acs.jmedchem.3c00050.
Jia-Jia Lang 1 2 3,  You Lv 4 5,  Bostjan Kobe 6,  Hongfei Chen 1,  Yan Tan 1,  Limei Chen 1,  Xuechuan Wang 4,  Pengbing Mi 1 3,  Xing Zheng 1 7,  Ying-Wu Lin 2 3
Affiliations

Affiliations

  • 1 Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
  • 2 Hengyang Medical College, School of Chemistry and Chemical Engineering, University of South China, Hengyang 421001, China.
  • 3 Key Lab of Protein Structure and Function of Universities in Hunan Province, University of South China, Hengyang 421001, China.
  • 4 College of Bioresources Chemical and Materials Engineering, Shaanxi University of Science & Technology, Xi'an, Shaanxi 710021, China.
  • 5 Xi'an Amazinggene Co., Ltd, Xi'an, Shaanxi 710026, China.
  • 6 School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Queensland 4072, Australia.
  • 7 Department of Pharmacy, Hunan Vocational College of Science and Technology, Changsha 410004, China.
PMID: 37163463 DOI: 10.1021/acs.jmedchem.3c00050
Abstract

Developing selective inhibitors for Janus kinase 1 (JAK1) is a significant focus for improving the efficacy and alleviating the adverse effects in treating immune-inflammatory diseases. Herein, we report the discovery of a series of C-5 pyrazole-modified pyrrolopyrimidine derivatives as JAK1-selective inhibitors. The potential hydrogen bond between the pyrazole group and E966 in JAK1 is the key point that enhances JAK1 selectivity. These compounds exhibit 10- to 20-fold JAK1 selectivity over JAK2 in Enzyme assays. Compound 12b also exhibits excellent JAK1 selectivity in Ba/F3-TEL-JAK cellular assays. Metabolism studies and the results of the hair growth model in mice indicate that compound 12b may be a viable lead compound for the development of highly JAK1-selective inhibitors for immune and inflammatory diseases.

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