1. Discovery of an Oxycyclohexyl Acid Lysophosphatidic Acid Receptor 1 (LPA 1 ) Antagonist BMS-986278 for the Treatment of Pulmonary Fibrotic Diseases.
- Author
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Cheng PTW, Kaltenbach RF 3rd, 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, and Murphy BJ
- 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
- Abstract
The oxycyclohexyl acid BMS-986278 ( 33 ) is a potent lysophosphatidic acid receptor 1 (LPA
1 ) 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).- Published
- 2021
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