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

Jia-Jia Lang; You Lv; Bostjan Kobe; Hongfei Chen; Yan Tan; Limei Chen; Xuechuan Wang; Pengbing Mi; Xing Zheng; Ying-Wu Lin

doi:10.1021/acs.jmedchem.3c00050

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

J Med Chem. 2023 May 25;66(10):6725-6742. doi: 10.1021/acs.jmedchem.3c00050. Epub 2023 May 10.

Authors

Jia-Jia Lang^{1

2

3}, You Lv^{4

5}, Bostjan Kobe⁶, Hongfei Chen¹, Yan Tan¹, Limei Chen¹, Xuechuan Wang⁴, Pengbing Mi^{1

3}, Xing Zheng^{1

7}, Ying-Wu Lin^{2

3}

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Janus Kinase 1
Janus Kinase 2
Janus Kinase 3
Janus Kinase Inhibitors* / pharmacology
Mice
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Pyrazoles* / pharmacology
Structure-Activity Relationship

Substances

Janus Kinase 1
Pyrazoles
Protein Kinase Inhibitors
Janus Kinase Inhibitors
Janus Kinase 2
Janus Kinase 3