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

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-beta-induced hepatic stellate cells (HSCs). Specifically, 31g significantly inhibited TGF-beta-induced migration of HSCs at 0.25 mu M in wound-healing assays.

Automated summary

JAK1 inhibition presents a promising therapeutic strategy for various diseases by designing selective inhibitors. In particular, the compound 31g showed potent activity against JAK1 and inhibited TGF-beta-induced HSCs migration effectively.