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

J Med Chem. 2021 Nov 11;64(21):15549-15581. doi: 10.1021/acs.jmedchem.1c01256. Epub 2021 Oct 28.


The oxycyclohexyl acid BMS-986278 (33) is a potent lysophosphatidic acid receptor 1 (LPA1) antagonist, with a human LPA1 Kb of 6.9 nM. The structure-activity relationship (SAR) studies starting from the LPA1 antagonist clinical compound BMS-986020 (1), which culminated in the discovery of 33, are discussed. The detailed in vitro and in vivo preclinical pharmacology profiles of 33, 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, 33 was advanced into clinical trials, including an ongoing Phase 2 clinical trial in patients with lung fibrosis (NCT04308681).

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Male
  • Mice
  • Molecular Structure
  • Pulmonary Fibrosis / drug therapy*
  • Pulmonary Fibrosis / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Lysophosphatidic Acid / antagonists & inhibitors*
  • Receptors, Lysophosphatidic Acid / metabolism
  • Structure-Activity Relationship


  • Receptors, Lysophosphatidic Acid

Associated data