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

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).

Discovery of the Novel, Orally Active, and Selective LPA1 Receptor Antagonist ACT-1016-0707 as a Preclinical Candidate for the Treatment of Fibrotic Diseases

“…Originally, the LPA-induced histamine release was characterized using a LPAR1/3 inhibitor . An acute LPA-induced histamine release assay in mice has been previously used to characterize the pharmaco­kinetic/​pharmaco­dynamic (PK/PD) relationship of different LPAR1 antagonists. − …”

Discovery of a Potent, Selective, and Orally Bioavailable Tool Compound for Probing the Role of Lysophosphatidic Acid Type 2 Receptor Antagonists in Fibrotic Disorders

“…Synthesis of (S) pyrimidin-4-yl)amino)propyl)piperidin-4-yl)benzenesulfonamide (11). Intermediate 65e (145 mg, 0.27 mmol) was reacted according to the general procedure D. The crude residue was purified by flash chromatography on silica-NH cartridge (eluent: cyclohexane/EtOAc from 100/0 to 40/60) to afford compound 11 (29 mg, 0.06 mmol, 22% yield) as a white solid.…”

“…10 The role of LPA 1 receptors in modulating lung fibrotic processes is well established in the clinic. Bristol Myers Squibb (among others) is studying the LPA 1 receptor antagonist BMS-986278 11 in phase 2 clinical trials for IPF and PF-ILD, while BMS-986020, 12 although discontinued in a phase 2 clinical trial in IPF patients for its hepatobiliary toxicity, showed a statistically significant reduction in the change from baseline of forced vital capacity compared to placebo.…”

Discovery of Chemical Scaffolds as Lysophosphatidic Acid Receptor 1 Antagonists: Virtual Screening, In Vitro Validation, and Molecular Dynamics Analysis

“…While several LPAR1 antagonists, including BMS-96278, BMS-986020, Ki16425, ONO-730043, and SAR-100842 (Figure ), have been identified to date, their structural similarities, as discussed in a recent review article, highlight the need for expanding the available repertoire of chemical templates capable of inducing LPAR1 antagonism. The importance of this diversification is underscored by BMS-986020’s hepatobiliary toxicity, which was found to be structure-dependent, a contrast to antagonists with distinct structural features that did not exhibit this toxicity .…”