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

  • Respir Res. 2025 Aug 31;26(1):265. doi: 10.1186/s12931-025-03340-4.
Michael Poon  1 ,  Kym Lorrain  2 ,  Alexander Broadhead  2 ,  Karin Stebbins  2 ,  Didier Bagnol  2 ,  Geraldine Edu  2 ,  Gregory Joseph  2 ,  Christopher Baccei  2 ,  Jeffrey Roppe  2 ,  Thomas Schrader  2 ,  Lino Valdez  2 ,  Yifeng Xiong  2 ,  Austin Chen  2 ,  Daniel Lorrain  2
Affiliations
  • 1. Contineum Therapeutics, 3565 General Atomics Court Suite 200, San Diego, CA, 92121, USA. [email protected].
  • 2. Contineum Therapeutics, 3565 General Atomics Court Suite 200, San Diego, CA, 92121, USA.
PMID: 40887574 DOI: 10.1186/s12931-025-03340-4
Abstract

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.

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