Discovery of GS-2278, a Potent and Selective LPAR1 Antagonist for the Treatment of Idiopathic Pulmonary Fibrosis

Tang, Doris T.; Du, Zhimin; Yang, Kin S.; Bestvater, Brian P.; Kaplan, Joshua; Neubig, Megan E.; Olen, Casey L.; Phillips, Bart; Wang, Peiyuan; Hudson, Thomas; Marchand, Bruno; Chan, Julie; Sharma, Monika; Hu, Yiding; Matles, Mike; Nejati, Elham; Chojnacka, Maja; Adams, Clifton; Pong, Cassie; Holsapple, Kevin; Budas, Grant; Tsui, Vickie; Venkataramani, Chandrasekar; Lazerwith, Scott E.; Notte, Gregory T.; Watkins, William J.; McGlinchey, Ellen; Zagorska, Anna; Farand, Julie

doi:10.1021/acs.jmedchem.4c02090

J. Med. Chem.

2024

DOI: 10.1021/acs.jmedchem.4c02090

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Discovery of GS-2278, a Potent and Selective LPAR1 Antagonist for the Treatment of Idiopathic Pulmonary Fibrosis

Doris T. Tang,

Zhimin Du,

Kin S. Yang

et al.

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Early Process Development of an LPAR1 Antagonist, GS-2278

Kadunce,

Wagner,

Cottell

et al. 2024

Org. Process Res. Dev.

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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 ethyl 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 alcohol. 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 preclinical and early clinical studies. This paper focuses on the development of conditions from the medicinal chemistry route to the Ph 1 manufacturing route.

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Early Process Development of an LPAR1 Antagonist, GS-2278

Kadunce,

Wagner,

Cottell

et al. 2024

Org. Process Res. Dev.

View full text Add to dashboard Cite

show abstract

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Discovery of GS-2278, a Potent and Selective LPAR1 Antagonist for the Treatment of Idiopathic Pulmonary Fibrosis

Cited by 1 publication

References 25 publications

Early Process Development of an LPAR1 Antagonist, GS-2278

Early Process Development of an LPAR1 Antagonist, GS-2278

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