GS-2278

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

(R)-1-(2,5-Difluoropyridin-3-yl)ethyl(1-methyl-4-(5-(2-(trifluoromethyl)pyrimidine-5-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (GS-2278) is a lysophosphatidic acid receptor 1 antagonist under development for the treatment of idiopathic pulmonary fibrosis.GS-2278 is assembled in a 9-step sequence.Initially, 2-bromo-5-fluoropyridine is metalated and trapped with Et difluoroacetate.Then, after condensation with tosyl hydrazide, Sakai cyclization with methylamine, and carboxylation with carbon dioxide, the triazole carboxylic acid core is generated.For the final assembly, the core is elaborated through a two-step hydroxamic acid formation and Lossen rearrangement to form an isocyanate which is trapped in situ by a chiral alc.The resulting carbamate is Boc-deprotected and subjected to amide coupling with a pyrimidine carboxylic acid to yield the active pharmaceutical ingredient.Process development was conducted to determine reaction and isolation conditions to enable scale-ups to support preclin. and early clin. studies.This paper focuses on the development of conditions from the medicinal chem. route to the Ph 1 manufacturing route.