Discovery and Biological Evaluation of N-Methyl-pyrrolo[2,3-b]pyridine-5-carboxamide Derivatives as JAK1-Selective Inhibitors
- 주제(기타) Chemistry, Medicinal
- 설명문(일반) [Park, Eunsun; Park, Jongmi; Choi, Sun; Kang, Soosung] Ewha Womans Univ, Coll Pharm, Seoul 03760, South Korea; [Park, Eunsun; Park, Jongmi; Choi, Sun; Kang, Soosung] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Seoul 03760, South Korea; [Lee, Sun Joo; Moon, Heegyum; Jeon, Hyeonho; Hwang, Ji Sun; Hwang, Hayoung; Hong, Ki Bum] Daegu Gyeongbuk Med Innovat Fdn DGMIF, New Drug Dev Ctr, Daegu 41061, South Korea; [Han, Seung-Hee] KOREA PHARMA Co Ltd, Cent Res Lab, Hwaseong Si 18622, Gyeonggi Do, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 AMER CHEMICAL SOC
- 발행년도 2021
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000181387
- 본문언어 영어
- Published As http://dx.doi.org/10.1021/acs.jmedchem.0c01026
초록/요약
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.
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