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Discovery of an Oxycyclohexyl Acid Lysophosphatidic Acid Receptor 1 (LPA 1 ) Antagonist BMS-986278 for the Treatment of Pulmonary Fibrotic Diseases.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2021 Nov 11; Vol. 64 (21), pp. 15549-15581. Date of Electronic Publication: 2021 Oct 28. - Publication Year :
- 2021
-
Abstract
- The oxycyclohexyl acid BMS-986278 ( 33 ) is a potent lysophosphatidic acid receptor 1 (LPA <subscript>1</subscript> ) antagonist, with a human LPA <subscript>1</subscript> K <subscript>b</subscript> of 6.9 nM. The structure-activity relationship (SAR) studies starting from the LPA <subscript>1</subscript> 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).
- Subjects :
- Animals
Dose-Response Relationship, Drug
Male
Mice
Molecular Structure
Pulmonary Fibrosis metabolism
Rats
Rats, Sprague-Dawley
Receptors, Lysophosphatidic Acid metabolism
Structure-Activity Relationship
Drug Discovery
Pulmonary Fibrosis drug therapy
Receptors, Lysophosphatidic Acid antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 64
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34709814
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.1c01256