Novel dual GPR40/GPR120 agonists DFL23915 and DFL24102 improve glucose tolerance and metabolic dysfunction

Current therapeutic strategies for metabolic disorders, including Type 2 Diabetes and obesity, often rely on incretin-based therapies, which, while effective, may not address all facets of the disease or have systemic side effects. Free fatty acid receptors GPR40 (FFAR1) and GPR120 (FFAR4) are crucial regulators of insulin and incretin secretion, as well as lipid metabolism. Targeting both receptors simultaneously offers a promising approach to modulate these complementary pathways, potentially providing more comprehensive metabolic control and addressing gaps in existing treatments by leveraging their roles in gut hormone release and nutrient sensing.

Researchers characterized three novel compounds, DFL23914, DFL23915, and DFL24102, derived from a validated chemical scaffold. In vitro, they assessed agonist activity at human GPR40 and GPR120 using Ca²⁺-dependent and β-arrestin signaling assays, GLP-1 secretion stimulation, hepatotoxicity, and cell permeability. In vivo, compounds were tested in Drosophila models of diet-induced metabolic dysfunction via chronic administration, evaluating locomotor performance, body weight gain, hyperglycemia, and triglyceride accumulation. Oral administration in mice was used to assess improved glucose tolerance in an oral glucose tolerance test (OGTT), measuring glycemic excursions.

All three compounds, DFL23914, DFL23915, and DFL24102, exhibited low-micromolar agonist activity at human GPR40 and GPR120, activating both Ca²⁺-dependent and β-arrestin signaling pathways. DFL24102 demonstrated the most balanced dual-agonist profile across these assays. In Drosophila models of diet-induced metabolic dysfunction, chronic administration of the compounds 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 confirmed significant stimulation of glucagon-like peptide-1 (GLP-1) secretion by DFL23914, DFL23915, and DFL24102, alongside an absence of hepatotoxicity. Cell 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. > The compounds demonstrated robust metabolic benefits through coordinated GPR40 and GPR120 activation, primarily via local intestinal activity, highlighting their potential as innovative therapies.