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

Lysophosphatidic acid (LPA) is a phospholipid activating different biological functions by binding to G protein-coupled receptors (LPA_1-6). Among these, the role of the LPA₁ 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 LPA₁ antagonists for the oral treatment of idiopathic pulmonary fibrosis with a focus on hepatobiliary safety. Compound <b>7</b> excelled in <i>in vitro</i> and <i>in vivo</i> efficacy, showing significant efficacy both in PD studies and in a rodent lung fibrosis model, with a promising <i>in vitro</i> hepatic safety profile. However, in a dose range finding (DRF) toxicity study, compound <b>7</b> did not ensure safety regarding potential hepatobiliary toxicity, leading to its development being halted.