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.

Peter T W Cheng ¹, Robert F Kaltenbach 3rd ¹, Hao Zhang ¹, Jun Shi ¹, Shiwei Tao ¹, Jun Li ¹, Lawrence J Kennedy ¹, Steven J Walker ¹, Yan Shi ¹, Ying Wang ¹, Suresh Dhanusu ², Ramesh Reddigunta ², Selvakumar Kumaravel ², Sutjano Jusuf ³, Daniel Smith ⁴, Subramaniam Krishnananthan ⁴, Jianqing Li ⁵, Tao Wang ⁶, Rebekah Heiry ⁶, Chi Shing Sum ⁶, Stephen S Kalinowski ⁷, Chen-Pin Hung ⁷, Ching-Hsuen Chu ⁷, Anthony V Azzara ⁷, Milinda Ziegler ⁷, Lisa Burns ⁷, Bradley A Zinker ⁷, Stephanie Boehm ⁷, Joseph Taylor ⁷, Julia Sapuppo ⁷, Kathy Mosure ⁸, Gerry Everlof ⁹, Victor Guarino ¹⁰, Lisa Zhang ¹⁰, Yanou Yang ¹¹, Qian Ruan ¹¹, Carrie Xu ¹², Atsu Apedo ¹³, Sarah C Traeger ¹⁴, Mary Ellen Cvijic ⁶, Kimberley A Lentz ¹⁰, Giridhar Tirucherai ¹⁵, Lakshmi Sivaraman ¹⁶, Jeffrey Robl ¹, Bruce A Ellsworth ¹, Glenn Rosen ⁷, David A Gordon ⁷, Matthew G Soars ⁸, Michael Gill ¹⁷, Brian J Murphy ⁷

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).

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-139853

BMS-986278

99.78%, LPL Receptor Antagonist

LPL Receptor

Others

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