Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic Properties

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Anders Højgaard Hansen, Eugenia Sergeev, Daniele Bolognini, Richard R. Sprenger, Jeppe Hvidtfeldt Ekberg, Christer S. Ejsing, Christine J. McKenzie, Elisabeth Rexen Ulven, Graeme Milligan, Trond Ulven

Free fatty acid receptor 2 (FFA2/GPR43) is a receptor for short-chain fatty acids reported to be involved in regulation of metabolism, appetite, fat accumulation, and inflammatory responses and is a potential target for treatment of various inflammatory and metabolic diseases. By bioisosteric replacement of the central pyrrolidine core of a previously disclosed FFA2 agonist with a synthetically more tractable thiazolidine, we were able to rapidly synthesize and screen analogues modified at both the 2- and 3-positions on the thiazolidine core. Herein, we report SAR exploration of thiazolidine FFA2 agonists and the identification of 31 (TUG-1375), a compound with significantly increased potency (7-fold in a cAMP assay) and reduced lipophilicity (50-fold reduced clogP) relative to the pyrrolidine lead structure. The compound has high solubility, high chemical, microsomal, and hepatocyte stability, and favorable pharmacokinetic properties and was confirmed to induce human neutrophil mobilization and to inhibit lipolysis in murine adipocytes.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume61
Issue number21
Pages (from-to)9534-9550
Number of pages17
ISSN0022-2623
DOIs
Publication statusPublished - 2018

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