Synthesis and structure-activity relationship evaluation of hypoglycemic activity of novel borneol and isoborneol containing (hydroxyphenyl)propanoic acids as FFAR1 agonists.

Free Fatty Acid Receptor-1 (FFAR1) agonists are promising candidates for the treatment of type 2 diabetes mellitus due to their glucose-lowering ability. Previously, we have shown that a benzyloxyphenylpropanoic acid derivative QS-619 (5d) containing a (-)-borneol residue acts as an effective FFAR1 agonist and exerts a hypoglycemic effect in mice. To establish the initial structure-activity relationships (SAR) for this chemotype, with a particular focus on the critical role of the terpene fragment's stereochemistry, we synthesized a series of its structural analogues with variations in the configuration of stereocenters and the position of substituents in the aromatic rings. The effect of borneol stereochemistry on hypoglycemic activity was studied. The cytotoxicity of the synthesized compounds was evaluated on HepG2 and HEK293T cell lines. The hypoglycemic activity of these compounds was assessed in an oral glucose tolerance test (OGTT) in mice at doses of 15 mg/kg and 30 mg/kg. The most potent hypoglycemic agent identified was compound 5e which bears a (+)-bornyl moiety. It demonstrated a strong effect at both doses, showed no cytotoxicity (CC₅₀ >100 µM), but exhibited acute toxicity at a dose of 1000 mg/kg. Compounds 5f and 5g, containing (-)- and (+)-isobornyl moieties, respectively, showed a less pronounced hypoglycemic effect compared to the bornyl derivatives 5d and 5e. The cyclohexyl derivative 5h was active only at the 30 mg/kg dose. Furthermore, co-administration of an FFAR1 antagonist was found to suppress the hypoglycemic activity of the studied compounds in the OGTT, supporting an FFAR1-mediated mechanism of action.