Refining free fatty acid receptor agonism for metabolic control: Pharmacological and functional features of novel dual GPR40/GPR120 ligands

Metabolic disorders require therapeutic strategies targeting complementary pathways beyond current incretin-based therapies. Free fatty acid receptors GPR40 (FFAR1) and GPR120 (FFAR4) regulate insulin and incretin secretion as well as lipid metabolism, supporting the development of dual agonists. Here, we characterized three novel compounds (DFL23914, DFL23915 and DFL24102) derived from a previously validated scaffold, combining in vitro pharmacology with in vivo functional analyses. All compounds exhibited low-micromolar agonist activity at human GPR40 and GPR120, activating both Ca²⁺-dependent and β-arrestin signaling pathways, with DFL24102 showing the most balanced dual-agonist profile. In Drosophila models of diet-induced metabolic dysfunction, chronic administration significantly improved locomotor performance, reduced body weight gain, and normalized hyperglycemia and triglyceride accumulation in both adult and larval stages, without affecting survival. In vitro assays demonstrated the significant stimulation of glucagon-like peptide-1 secretion by DFL23914, DFL23915, and DFL24102 as well as the absence of hepatotoxicity, while cells permeability and mouse pharmacokinetics revealed minimal systemic exposure, supporting a gut-restricted mechanism of action. Consistently, oral administration in mice improved glucose tolerance in an oral glucose tolerance test, with significant reductions in glycemic excursions, particularly for DFL23915 and DFL24102. Overall, these findings indicate that dual GPR40/GPR120 agonists of this chemical series exert robust metabolic benefits through coordinated receptor activation and local intestinal activity. This study further supports dual FFAR targeting as a promising pharmacological approach and identifies leading candidates for the development of innovative therapies for metabolic disorders.