Identification and Biological Evaluation of a Potent and Selective JAK1 Inhibitor for the Treatment of Pulmonary Fibrosis,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Identification and Biological Evaluation of a Potent and Selective JAK1 Inhibitor for the Treatment of Pulmonary Fibrosis
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-11-30 , 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

Affiliation

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.

中文翻译：

用于治疗肺纤维化的有效选择性 JAK1 抑制剂的鉴定和生物学评价

Janus 激酶 1 (JAK1) 通过 JAK/STAT 信号通路在调节炎症和纤维化中发挥关键作用，使其成为相关疾病的有希望的靶标。在本研究中，我们探索了N -甲基 1 H -吡咯并[2,3- b ]吡啶-5-羧酸酯核心的修饰，从而鉴定出 4-(((2 S ,4 S )-1- (4-三氟甲基)-2-甲基哌啶-4-基)氨基) -N-甲基-1H-吡咯并[2,3- b ]吡啶-5-甲酰胺 ( 36b ) 作为高效、选择性 JAK1 抑制剂。化合物36b对 JAK1 表现出令人印象深刻的 IC ₅₀值（0.044 nM），并且表现出比 JAK2、JAK3 和 TYK2 分别高 382 倍、210 倍和 1325 倍的显着选择性。激酶组检测进一步证实了其特异性，基于细胞的实验证实了其抑制人 L-132 或 SK-MES-1 细胞中 JAK1-STAT 磷酸化的功效。药代动力学研究表明，化合物36b 的口服生物利用度超过 36%。在博莱霉素诱导的纤维化小鼠模型中，化合物36b显着降低 STAT3 磷酸化，从而改善体重并减少胶原蛋白沉积，所有这些都没有明显的副作用。

更新日期：2023-11-30

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南