Discovery of an Oxycyclohexyl Acid Lysophosphatidic Acid Receptor 1 (LPA₁) Antagonist BMS-986278 for the Treatment of Pulmonary Fibrotic Diseases

Abstract

The oxycyclohexyl acid BMS-986278 (<b>33</b>) is a potent lysophosphatidic acid receptor 1 (LPA₁) antagonist, with a human LPA₁ <i>K</i>_b of 6.9 nM. The structure-activity relationship (SAR) studies starting from the LPA₁ antagonist clinical compound BMS-986020 (<b>1</b>), which culminated in the discovery of <b>33</b>, are discussed. The detailed in vitro and in vivo preclinical pharmacology profiles of <b>33,</b> as well as its pharmacokinetics/metabolism profile, are described. On the basis of its in vivo efficacy in rodent chronic lung fibrosis models and excellent overall ADME (absorption, distribution, metabolism, excretion) properties in multiple preclinical species, <b>33</b> was advanced into clinical trials, including an ongoing Phase 2 clinical trial in patients with lung fibrosis (NCT04308681).