Discovery of an Oxycyclohexyl Acid Lysophosphatidic Acid Receptor 1 (LPA<sub>1</sub>) Antagonist BMS-986278 for the Treatment of Pulmonary Fibrotic Diseases.
Cheng PTW, Kaltenbach RF, Zhang H, Shi J, Tao S, Li J, Kennedy LJ, Walker SJ, Shi Y, Wang Y, Dhanusu S, Reddigunta R, Kumaravel S, Jusuf S, Smith D, Krishnananthan S, Li J, Wang T, Heiry R, Sum CS, Kalinowski SS, Hung CP, Chu CH, Azzara AV, Ziegler M, Burns L, Zinker BA, Boehm S, Taylor J, Sapuppo J, Mosure K, Everlof G, Guarino V, Zhang L, Yang Y, Ruan Q, Xu C, Apedo A, Traeger SC, Cvijic ME, Lentz KA, Tirucherai G, Sivaraman L, Robl J, Ellsworth BA, Rosen G, Gordon DA, Soars MG, Gill M, Murphy BJ.
The oxycyclohexyl acid BMS-986278 (<b>33</b>) is a potent lysophosphatidic acid receptor 1 (LPA<sub>1</sub>) antagonist, with a human LPA<sub>1</sub> <i>K</i><sub>b</sub> of 6.9 nM. The structure-activity relationship (SAR) studies starting from the LPA<sub>1</sub> antagonist clinical compound BMS-986020 (<b>1</b>), which culminated in the discovery of <b>33</b>, are discussed. The detailed in vitro and in vivo preclinical pharmacology profiles of <b>33,</b> 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, <b>33</b> was advanced into clinical trials, including an ongoing Phase 2 clinical trial in patients with lung fibrosis (NCT04308681).