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

• Published in: Journal of medicinal chemistry Vol. 64; no. 2; pp. 958 - 979
• Main Authors: Park, Eunsun, Lee, Sun Joo, Moon, Heegyum, Park, Jongmi, Jeon, Hyeonho, Hwang, Ji Sun, Hwang, Hayoung, Hong, Ki Bum, Han, Seung-Hee, Choi, Sun, Kang, Soosung
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.01.2021; Amer Chemical Soc
• Subjects: Animals; Cell Line; Chemistry, Medicinal; Drug Design; Drug Discovery; Gene Expression Regulation - drug effects; Hepatic Stellate Cells - drug effects; Humans; Janus Kinase 1 - antagonists & inhibitors; Life Sciences & Biomedicine; Liver Cirrhosis - drug therapy; Liver Cirrhosis - genetics; Liver Cirrhosis - pathology; Mice; Models, Molecular; Pharmacology & Pharmacy; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - pharmacology; Science & Technology; Structure-Activity Relationship; Substrate Specificity; Transforming Growth Factor beta - antagonists & inhibitors; Wound Healing - drug effects; RHEUMATOID-ARTHRITIS; MIGRATION; CELLS; DESIGN; POTENT; EFFICACY; AUTOIMMUNE-DISEASES; KINASE; JAK INHIBITION; IDENTIFICATION
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01026

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.