Discovery of\nGS-2278, a Potent and Selective LPAR1 Antagonist for the Treatment of Idiopathic\nPulmonary Fibrosis

We describe the discovery and preclinical characterization\nof a\npotent and selective lysophosphatidic acid receptor 1 (LPAR1) antagonist\nwith a direct-acting antifibrotic mechanism. <b>18a</b> was\ninitially identified as a potent non-carboxylic acid LPAR1 antagonist\nin an LPA-induced myocardin-related transcription factor A (MRTF-A)\nnuclear translocation assay. Modifications to the aromatic elements\nin the structure allowed for improvements in metabolic stability and\nthe mitigation of GSH adduct formation, but in vitro to in vivo clearance\ndisconnects were observed with several potent sulfonamides (e.g., <b>27b</b>) across preclinical species. Through modification of the\nsulfonamide, <b>42</b> (<b>GS-2278</b>) emerged as a potent\nLPAR1 antagonist with a suitable in vitro profile and desirable pharmacokinetic\nproperties for oral QD dosing. <b>GS-2278</b> dose-dependently\nblocked LPA-induced histamine release and demonstrated efficacy in\nan interventional model of bleomycin-induced lung fibrosis. However,\nCNS-related toxicity was observed in dogs, and based on these findings,\nthe clinical development of <b>GS-2278</b> for IPF was halted.