Identification and Biological Evaluation of a Potent and Selective JAK1 Inhibitor for the Treatment of Pulmonary Fibrosis

  • J Med Chem. 2023 Dec 14;66(23):16342-16363. doi: 10.1021/acs.jmedchem.3c01712.
Eunsun Park  1 ,  Seolhee Park  1 ,  Sun Joo Lee  2 ,  Dayeon Jeong  1 ,  Hee Jin  1 ,  Heegyum Moon  2 ,  Boksik Cha  2 ,  Dayea Kim  2 ,  Seonghee Ma  1 ,  Wonhyo Seo  1 ,  Seung-Hee Han  3 ,  Yun-Sil Lee  1 ,  Soosung Kang  1
Affiliations
  • 1. College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
  • 2. New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Republic of Korea.
  • 3. Central Research Laboratory, KOREA PHARMA Co. Ltd., Jeyakgongdan 3-gil, Hyangnam-eup, Hwaseong-si, Gyeonggi-do 16630, Republic of Korea.
PMID: 38031930 DOI: 10.1021/acs.jmedchem.3c01712
Abstract

Janus kinase 1 (JAK1) plays a pivotal role in regulating inflammation and fibrosis via the JAK/STAT signaling pathway, making it a promising target for associated diseases. In this study, we explored the modification of an N-methyl 1H-pyrrolo[2,3-b]pyridine-5-carboxylate core, leading to the identification of 4-(((2S,4S)-1-(4-trifluoromethyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (36b) as a highly potent and selective JAK1 Inhibitor. Compound 36b exhibited an impressive IC50 value of 0.044 nM for JAK1 and demonstrated remarkable selectivity of 382-fold, 210-fold, and 1325-fold specificity over JAK2, JAK3, and Tyk2, respectively. The kinase panel assays further confirmed its specificity, and cell-based experiments established its efficacy in inhibiting JAK1-STAT phosphorylation in human L-132 or SK-MES-1 cells. Pharmacokinetic studies revealed that compound 36b boasts an oral bioavailability exceeding 36%. In a bleomycin-induced fibrosis mouse model, compound 36b significantly reduced STAT3 phosphorylation, resulting in improvement in body weight and reduced Collagen deposition, all achieved without significant side effects.

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