Discovery of potent anti-idiopathic pulmonary fibrosis (IPF) agents based on an o-aminopyridinyl alkynyl scaffold.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with high mortality and limited treatment options. Targeting multiple kinase-driven pathological processes offers a promising strategy. Using epithelial-mesenchymal transition (EMT) phenotypic screening, we optimized a series of o-aminopyridinyl alkynyl compounds derived from CSF-1R relatively selective inhibitor, compound 1, through a structure-activity relationship (SAR) study, integrating liver and kidney cytotoxicity evaluations. Compound 22, emerged as the potent antifibrotic candidate, exhibiting low cytotoxic effects against human kidney (HEK293) and hepatocyte (L02) cell lines, and minimal hERG inhibition. In addition, 22 showed significant inhibition against other IPF-related processes, including fibroblast-to-myofibroblast transition (FMT)-driven fibrosis in both human fetal lung fibroblasts cell line (HFL1) and primary human lung fibroblasts (HLFs), as well as pro-fibrotic M2 polarization. In vivo, compound 22 exhibited the acceptable PK properties and low toxicity profiles. In addition, oral administration of 22 demonstrated superior anti-fibrotic efficacy compared to Nintedanib, significantly attenuating bleomycin-induced lung fibrosis, reducing inflammation and pro-fibrotic M2-associated cytokine levels, and improving lung function. Preliminary kinase profiling indicates that compound 22 likely targets CSF-1R, PDGFR-α and Src family kinases to inhibit IPF progression, while sparing VEGFRs, FGFRs and Abl to minimize off-target toxicity commonly associated with multi-kinase inhibitor treatment. These findings highlight the advantages and therapeutic potential of a multi-kinase targeting strategy, enabling selective inhibition key IPF-associated kinases to develop more effective and safer anti-IPF agents.