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

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.