Targeting Autotaxin with imidazole- and Triazolyl-based inhibitors: Biological insights from in vitro and in vivo studies in pulmonary fibrosis

Abstract

Autotaxin (ATX) is a key enzyme in producing lysophosphatidic acid (LPA), a lipid involved in fibrosis. This study reports the synthesis and evaluation of novel ATX inhibitors containing zinc-binding imidazole or triazole motif with piperidine spacers. Compound 27a exhibited strong ATX inhibition (IC<inf>50</inf> = 57 nM) in human plasma and demonstrated efficacy in cellular and animal fibrosis models. In vitro ADME/T studies showed favorable liver microsomal stability, minimal hERG binding, and acceptable PK parameters. In vivo, 27a significantly reduced plasma LPA levels and downregulated fibrosis-related pathways, including p-ERK, p-P38, and p-JNK. It also inhibited cell migration and collagen gel contraction without cytotoxicity in fibrotic cells. In a bleomycin-induced pulmonary fibrosis model, 27a reduced collagen deposition, LPAR1, and p-ERK expression, while decreasing mRNA levels of α-SMA, Col1A1, and pro-inflammatory markers IL-6, IL-1β, and INFγ. These findings position 27a as a promising ATX inhibitor with therapeutic potential for fibrosis-related diseases. © 2025 Elsevier B.V., All rights reserved.