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

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).环己氧基酸类化合物BMS-986278（编号33）是一种强效溶血磷脂酸受体1（lysophosphatidic acid receptor 1，LPA1）拮抗剂，其人源LPA1的Kb值为6.9 nM。 本文探讨了以LPA1拮抗剂临床候选化合物BMS-986020（编号1）为起始点开展的构效关系（structure–activity relationship，SAR）研究，该研究最终成功发现了化合物33。本文同时详述了化合物33的体外与体内临床前药理学特征，以及其药代动力学与代谢特征谱。基于其在啮齿类慢性肺纤维化模型中的体内药效，以及在多种临床前物种中展现出的优异ADME（吸收、分布、代谢、排泄）整体特性，化合物33已被推进至临床试验阶段，其中包含一项正在开展的肺纤维化患者II期临床试验（NCT04308681）。