化学
磷酸化
激酶
博莱霉素
贾纳斯激酶
吡啶
药理学
癌症研究
生物化学
内科学
生物
医学
药物化学
化疗
作者
Eunsun Park,Seol-Hee Park,Sun Joo Lee,Dayeon Jeong,Hee Kyung Jin,Heegyum Moon,Boksik Cha,Dayea Kim,Sisi Ma,Wonhyo Seo,Seung-Hee Han,Yun Sil Lee,Soosung Kang
标识
DOI:10.1021/acs.jmedchem.3c01712
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI