Synthesis and evaluation of 1H-pyrrolo[2,3-b]pyridine derivatives as novel immunomodulators targeting Janus kinase 3

Chemical & Pharmaceutical Bulletin
Yutaka NakajimaTakayuki Inoue

Abstract

Janus kinases (JAKs) have been known to play crucial roles in modulating a number of inflammatory and immune mediators. Here, we describe a series of 1H-pyrrolo[2,3-b]pyridine derivatives as novel immunomodulators targeting JAK3 for use in treating immune diseases such as organ transplantation. In the chemical modification of compound 6, the introduction of a carbamoyl group to the C5-position and substitution of a cyclohexylamino group at the C4-position of the 1H-pyrrolo[2,3-b]pyridine ring led to a large increase in JAK3 inhibitory activity. Compound 14c was identified as a potent, moderately selective JAK3 inhibitor, and the immunomodulating effect of 14c on interleukin-2-stimulated T cell proliferation was shown. Docking calculations and WaterMap analysis of the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives were conducted to confirm the substituent effects on JAK3 inhibitory activity.

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Citations

Jan 10, 2017·Expert Opinion on Therapeutic Patents·Mohammed I El-Gamal, Hanan S Anbar
Feb 16, 2019·Scientific Reports·Satish Kumar RajasekharanJintae Lee
Mar 31, 2021·Journal of Medicinal Chemistry·Andrew C FlickChristopher J O'Donnell
Oct 9, 2021·Journal of Medicinal Chemistry·Cecilia C Ayala-AguileraAsier Unciti-Broceta

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