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

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 1 H -pyrrolo[2,3- b ]pyridine-5-carboxylate core, leading to the identification of 4-(((2 S ,4 S )-1-(4-trifluoromethyl)-2-methylpiperidin-4-yl)amino)- N -methyl-1 H -pyrrolo[2,3- b ]pyridine-5-carboxamide ( 36b ) as a highly potent and selective JAK1 inhibitor. Compound 36b exhibited an impressive IC 50 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.