BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive form of interstitial lung disease (ILD) characterized by significant extracellular matrix deposition, alveolar damage, and tissue remodeling. Antagonists against the G-protein coupled receptor, lysophosphatidic acid receptor 1 (LPAR1) have shown efficacy in lung fibrosis preclinically and clinically. Here, we profile PIPE-791, a small molecule, orally bioavailable LPAR1 receptor antagonist, and show its effectiveness in several lung fibrosis-related contexts. METHODS: In vitro, we used human lung fibroblasts and precision cut lung slices (PCLS) derived from donors with pulmonary fibrosis to test PIPE-791 efficacy in reducing markers of fibrosis. In vivo, we used bleomycin-induced lung fibrosis models to demonstrate PIPE-791 efficacy. RESULTS: In vitro PIPE-791 reduced LPA-induced collagen expression (IC 1.1 nM) in human lung fibroblasts. We also show that LPAR1 is elevated in IPF lung tissue and that PIPE-791 significantly reduced several markers of lung fibrosis in PCLS as measured by gene expression and secreted biomarkers. Using in vivo receptor occupancy, we found that PIPE-791 has long association kinetics resulting in a 20-fold increase in potency when dosed 3 versus 24 h prior to radioligand administration. At 3 mg/kg, PIPE-791 was effective in significantly reducing markers of fibrosis and collagen expression in mouse bleomycin models. CONCLUSIONS: We show that PIPE-791 effectively reduces fibrosis and fibrotic markers in vitro and in vivo and that it has slow association and dissociation kinetics. Taken together, our data support clinical testing of PIPE-791 in the context of fibrotic conditions such as IPF.