GPR-120 agonist (Axxam)

Extensive research has confirmed that omega-3 fatty acids provide cardiovascular protection primarily by activating the G protein-coupled receptor 120 (GPR120) signaling pathway. However, natural activators of this receptor often lack sufficient strength and precision. TUG-891, a recently synthesized selective GPR120 activator, has displayed significant therapeutic potential in multiple disease. This investigation seeks to evaluate the neuroprotective effects of TUG-891 against ischemic cerebral injury. To this end, an in vivo murine model of distal middle cerebral artery occlusion (dMCAO) was employed, alongside an in vitro model utilizing oxygen-glucose deprivation/reperfusion in HT22 ​cells. The results indicated that TUG-891 significantly enhanced neurological function, reduced the volume of cerebral infarction, and alleviated pathological damage following dMCAO. Moreover, TUG-891 demonstrated a significant reduction in oxidative stress levels, a decrease of markers related to endoplasmic reticulum (ER) stress, and the modulation of critical apoptotic regulators, thereby inhibiting apoptosis in both in vivo and in vitro settings. Additionally, TUG-891 was found to affect the PI3K/Akt signaling pathway, with the application of the inhibitor LY294002 negating the protective effects of TUG-891 in vitro. This comprehensive study reveals TUG-891's therapeutic potential for ischemic stroke through multi-target mechanisms involving oxidative stress mitigation, ER stress regulation, and survival pathway activation. The consistent neuroprotection observed across biological models underscores its translational value for further clinical development.

Type 2 diabetes mellitus (T2DM) affects over 530 million individuals globally, and is projected to reach 783 million by 2045, necessitating novel therapeutic strategies beyond current options. G-protein-coupled receptor 120 (GPR120), a lipid sensor regulating insulin sensitivity and inflammation, has gained attention as a promising target.

This review evaluates 25 patents and peer-reviewed studies (2020-2025) on GPR120 agonists. It highlights potent thiophene derivatives (EC₅₀ < 50 nM), sulfonamides, and stable fatty acid mimetics. Special attention is given to β-arrestin-biased agonists that improve glucose control (25% AUC reduction), improve insulin sensitivity (30% glucose drop), and reduce inflammation (40% TNFα inhibition). These compounds enhance GLP-1 secretion (a 2-fold increase), offering triple therapeutic benefits for diabetes. Sources were identified through a structured search of recent scientific literature and databases.

GPR120 agonists, particularly β-arrestin-biased ligands, hold significant potential for T2DM treatment by modulating glucose homeostasis and inflammation. However, challenges like receptor desensitization and translational barriers such as species-specific receptor expression, off-target activity, and suboptimal pharmacokinetics must be addressed. Future research should optimize drug design to enhance efficacy and safety, paving the way for novel metabolic disorder therapies.