Novel Cyclohexyl Amido Acid Antagonists of Lysophosphatidic Acid Type 1 Receptor for the Treatment of Pulmonary Fibrosis

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2025 Feb 19

PMID 39967626

Authors

Marta Giuliani

Andrea Rizzi

Mafalda Pagano

Luca F Raveglia

Francesca Saccani

Maria Rosaria Di Lascia

Margherita Interlandi

Tonia Simona Nardella

Gessica Marchini

Annalisa Murgo

Laura Tigli

Alice Pappani

Anna Maria Capelli

Sergio Xanxo Fernandez

Paola Puccini

Gino Villetti

Maurizio Civelli

Claudia Beato

Elisa Moro

Claudia Mundi

Rosaria Remelli

Elisabetta Armani

Affiliations

Soon will be listed here.

Abstract

Lysophosphatidic acid (LPA) is a phospholipid activating different biological functions by binding to G protein-coupled receptors (LPA). Among these, the role of the LPA receptor in modulating fibrotic processes is well-known, making it a therapeutic target for pulmonary fibrosis and other fibrotic disorders. Herein we report the search for a new class of LPA antagonists for the oral treatment of idiopathic pulmonary fibrosis with a focus on hepatobiliary safety. Compound excelled in and efficacy, showing significant efficacy both in PD studies and in a rodent lung fibrosis model, with a promising hepatic safety profile. However, in a dose range finding (DRF) toxicity study, compound did not ensure safety regarding potential hepatobiliary toxicity, leading to its development being halted.

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