Discovery of a Potent, Selective, and Orally Bioavailable Tool Compound for Probing the Role of Lysophosphatidic Acid Type 2 Receptor Antagonists in Fibrotic Disorders.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by lung fibrosis leading to an irreversible decline of lung function. Current antifibrotic drugs on the market slow down but do not prevent the progression of the disease and are associated with tolerability issues. The involvement of lysophosphatidic acid receptor 2 (LPA) in IPF is supported by LPA knockdown studies. To further validate the role of LPA receptors in modulating IPF and potentially other fibrotic processes, a potent and selective LPA receptor antagonist with a good pharmacokinetic (PK) profile is needed. Herein, we report the medicinal chemistry exploration that led to the discovery of a new class of highly potent and selective LPA antagonists. Among them, compound exhibits excellent potency, selectivity, and oral PK profile, making it a suitable tool for probing the involvement of LPA receptors in IPF and other fibrotic processes.