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

      1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 2 , 2 , 2 , 3 , 4 , 4 , 5 , 6 , 6 , 6 , 7 , 7 , 7 , 7 , 7 , 7 , 7 , 7 , 7 , 7 , 8 , 9 , 10 , 10 , 11 , 11 , 12 , 13 , 14 , 6 , 10 , 15 , 16 , 1 , 1 , 7 , 7 , 8 , 17 , 7
      Journal of medicinal chemistry
      American Chemical Society (ACS)

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          Abstract

          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).

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          Author and article information

          Journal
          J Med Chem
          Journal of medicinal chemistry
          American Chemical Society (ACS)
          1520-4804
          0022-2623
          Nov 11 2021
          : 64
          : 21
          Affiliations
          [1 ] Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
          [2 ] Biocon-Bristol Myers Squibb Research & Development Center, Bangalore 560099, India.
          [3 ] Computer Aided Drug Design, Molecular Structure & Design, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
          [4 ] Discovery Chemistry Synthesis, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
          [5 ] Discovery Chemistry Synthesis, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Cambridge, Massachusetts 02140, United States.
          [6 ] Lead Evaluation, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
          [7 ] Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
          [8 ] Metabolism & Pharmacokinetics, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Cambridge, Massachusetts 02140, United States.
          [9 ] Pharmaceutics, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
          [10 ] Metabolism & Pharmacokinetics, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
          [11 ] Biotransformation, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
          [12 ] Bioanalytical Chemistry, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
          [13 ] Discovery Analytical Sciences, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
          [14 ] Discovery Analytical Sciences, Small Molecule Drug Discovery, Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
          [15 ] Clinical Pharmacology, Immunology, Cardiovascular and Fibrosis, Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-5326, United States.
          [16 ] Nonclinical Safety Evaluation, Research & Development, Bristol Myers Squibb Company, New Brunswick, New Jersey 08903-0191, United States.
          [17 ] Discovery Toxicology, Preclinical Candidate Optimization, Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
          Article
          10.1021/acs.jmedchem.1c01256
          34709814
          34771878-fce5-412c-9f6f-0bd5a18dba9d
          History

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