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Background <p>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.</p> Methods <p>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.</p> Results <p>In vitro PIPE-791 reduced LPA-induced collagen expression (IC<sub>50</sub> 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&#xa0;h prior to radioligand administration. At 3&#xa0;mg/kg, PIPE-791 was effective in significantly reducing markers of fibrosis and collagen expression in mouse bleomycin models.</p> Conclusions <p>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.</p>

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The LPAR1 antagonist, PIPE-791 produces antifibrotic effects in models of lung fibrosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月31日

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  • Michael Poon,
  • Kym Lorrain,
  • Alexander Broadhead,
  • Karin Stebbins,
  • Didier Bagnol,
  • Geraldine Edu,
  • Gregory Joseph,
  • Christopher Baccei,
  • Jeffrey Roppe,
  • Thomas Schrader,
  • Lino Valdez,
  • Yifeng Xiong,
  • Austin Chen,
  • Daniel Lorrain

摘要

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 (IC50 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.