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Identification and Biological Evaluation of a Potent and Selective JAK1 Inhibitor for the Treatment of Pulmonary Fibrosis
- Title
- Identification and Biological Evaluation of a Potent and Selective JAK1 Inhibitor for the Treatment of Pulmonary Fibrosis
- Authors
- Park; Eunsun; Seolhee; Lee; Sun Joo; Jeong; Dayeon; Jin; Hee; Moon; Heegyum; Cha; Boksik; Kim; Dayea; Ma; Seonghee; Seo; Wonhyo; Han; Seung-Hee; Yun-Sil; Kang; Soosung
- Ewha Authors
- 이윤실; 강수성; 서원효; 진희
- SCOPUS Author ID
- 이윤실
; 강수성
; 서원효
; 진희![scopus](/images/layout/icon2.png)
- Issue Date
- 2023
- Journal Title
- Journal of Medicinal Chemistry
- ISSN
- 0022-2623
- Citation
- Journal of Medicinal Chemistry vol. 66, no. 23, pp. 16342 - 16363
- Publisher
- American Chemical Society
- Indexed
- SCIE; SCOPUS
![scopus](/images/layout/scopus2.gif)
- Document Type
- Article
- 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. © 2023 American Chemical Society.
- DOI
- 10.1021/acs.jmedchem.3c01712
- Appears in Collections:
- 약학대학 > 약학과 > Journal papers
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