Discovery of an Oxycyclohexyl Acid Lysophosphatidic Acid Receptor 1 (LPA1) Antagonist BMS-986278 for the Treatment of Pulmonary Fibrotic Diseases.
Peter T W ChengRobert F KaltenbachHao ZhangJun ShiShiwei TaoJun LiLawrence J KennedySteven J WalkerYan ShiYing WangSuresh DhanusuRamesh ReddiguntaSelvakumar KumaravelSutjano JusufDaniel SmithSubramaniam KrishnananthanJianqing LiTao WangRebekah HeiryChi Shing SumStephen S KalinowskiChen-Pin HungChing-Hsuen ChuAnthony V AzzaraMilinda ZieglerLisa BurnsBradley A ZinkerStephanie BoehmJoseph TaylorJulia SapuppoKathy MosureGerry EverlofVictor GuarinoLisa ZhangYanou YangQian RuanCarrie XuAtsu ApedoSarah C TraegerMary Ellen CvijicKimberley A LentzGiridhar TirucheraiLakshmi SivaramanJeffrey RoblBruce Alan EllsworthGlenn RosenDavid A GordonMatthew G SoarsMichael GillBrian J MurphyPublished in: Journal of medicinal chemistry (2021)
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).