Discovery and Biological Evaluation of N-Methyl-pyrrolo[2,3- b]pyridine-5-carboxamide Derivatives as JAK1-Selective Inhibitors

Eunsun Park, Sun Joo Lee, Heegyum Moon, Jongmi Park, Hyeonho Jeon, Ji Sun Hwang, Hayoung Hwang, Ki Bum Hong, Seung Hee Han, Sun Choi, Soosung Kang

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Janus kinase 1 (JAK1) plays a key role in most cytokine-mediated inflammatory and autoimmune responses through JAK/STAT signaling; thus, JAK1 inhibition is a promising therapeutic strategy for several diseases. Analysis of the binding modes of current JAK inhibitors to JAK isoforms allowed the design of N-alkyl-substituted 1-H-pyrrolo[2,3-b] pyridine carboxamide as a JAK1-selective scaffold, and the synthesis of various methyl amide derivatives provided 4-((cis-1-(4-chlorobenzyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (31g) as a potent JAK1-selective inhibitor. In particular, the (S,S)-enantiomer of 31g (38a) exhibited excellent potency for JAK1 and selectivity over JAK2, JAK3, and TYK2. On investigating the effect of 31g on hepatic fibrosis, it was found that it reduces the proliferation and fibrogenic gene expression of TGF-β-induced hepatic stellate cells (HSCs). Specifically, 31g significantly inhibited TGF-β-induced migration of HSCs at 0.25 μM in wound-healing assays.

Original languageEnglish
Pages (from-to)958-979
Number of pages22
JournalJournal of Medicinal Chemistry
Volume64
Issue number2
DOIs
StatePublished - 28 Jan 2021

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