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

Peter T W Cheng¹, Robert F Kaltenbach 3rd¹, Hao Zhang¹, Jun Shi¹, Shiwei Tao¹, Jun Li¹, Lawrence J Kennedy¹, Steven J Walker¹, Yan Shi¹, Ying Wang¹, Suresh Dhanusu², Ramesh Reddigunta², Selvakumar Kumaravel², Sutjano Jusuf³, Daniel Smith⁴, Subramaniam Krishnananthan⁴, Jianqing Li⁵, Tao Wang⁶, Rebekah Heiry⁶, Chi Shing Sum⁶, Stephen S Kalinowski⁷, Chen-Pin Hung⁷, Ching-Hsuen Chu⁷, Anthony V Azzara⁷, Milinda Ziegler⁷, Lisa Burns⁷, Bradley A Zinker⁷, Stephanie Boehm⁷, Joseph Taylor⁷, Julia Sapuppo⁷, Kathy Mosure⁸, Gerry Everlof⁹, Victor Guarino¹⁰, Lisa Zhang¹⁰, Yanou Yang¹¹, Qian Ruan¹¹, Carrie Xu¹², Atsu Apedo¹³, Sarah C Traeger¹⁴, Mary Ellen Cvijic⁶, Kimberley A Lentz¹⁰, Giridhar Tirucherai¹⁵, Lakshmi Sivaraman¹⁶, Jeffrey Robl¹, Bruce A Ellsworth¹, Glenn Rosen⁷, David A Gordon⁷, Matthew G Soars⁸, Michael Gill¹⁷, Brian J Murphy⁷

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.

PMID: 34709814
DOI: 10.1021/acs.jmedchem.1c01256

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

Peter T W Cheng et al. J Med Chem. 2021.

. 2021 Nov 11;64(21):15549-15581.

doi: 10.1021/acs.jmedchem.1c01256. Epub 2021 Oct 28.

Authors

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.

PMID: 34709814
DOI: 10.1021/acs.jmedchem.1c01256

Abstract

The oxycyclohexyl acid BMS-986278 (33) is a potent lysophosphatidic acid receptor 1 (LPA₁) antagonist, with a human LPA₁ K_b 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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Discovery of an Oxycyclohexyl Acid Lysophosphatidic Acid Receptor 1 (LPA₁) Antagonist BMS-986278 for the Treatment of Pulmonary Fibrotic Diseases

Affiliations

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

Authors

Affiliations

Abstract

MeSH terms

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Associated data

LinkOut - more resources

Full Text Sources

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Chemical Information

Medical

Molecular Biology Databases

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