TAK875（CAS:1000413-72-8)

TAK-875, generic name Fasiglifam, CAS number 1000413-72-8, was originally designed and synthesized by Takeda Pharmaceuticals. It is the world’s first selective GPR40 (FFAR1 free fatty acid receptor 1) agonist to complete Phase 2 trials and advance into Phase 3 clinical development, pioneering an entirely new therapeutic pathway targeting free fatty acid receptors for glycemic control. At present, it serves as an irreplaceable standard research tool API in metabolic pharmacology and target medicinal chemistryACS Public.... It appears as white to off-white solid with molecular formula C₂₉H₃₂O₇S and stable physicochemical properties for long-term storage under low temperature and light shielding. It features single chiral configuration with HPLC purity above 99%, strict control over related impurities, heavy metals and residual solvents, fully matching high-end research demands including in vitro cell binding assays, primary pancreatic islet function detection, diabetic animal model construction, high-throughput compound screening and target crystal structure verification. Supply specifications range from milligram to kilogram scale to cover full R&D workflows of universities, CRO laboratories and innovative pharmaceutical enterprises.

In terms of core pharmacological mechanism, GPR40 is a G-protein coupled receptor highly expressed on pancreatic β-cells, with endogenous long-chain free fatty acids as natural ligands that amplify glucose-stimulated insulin secretion, representing an independent novel hypoglycemic target distinct from DPP4, SGLT2 and sulfonylurea agentsPMC. As an allosteric selective agonist with EC50 ranging 26–72 nM, TAK-875 efficiently binds the transmembrane pocket of GPR40 and activates PLC-PKC signaling cascade to trigger insulin exocytosis exclusively under hyperglycemic conditions; no insulin release is induced under normal fasting glucose, fundamentally eliminating spontaneous hypoglycemia risks common to sulfonylureas. Phase 2 12-week clinical data demonstrated approximately 1.1% HbA1c reduction, comparable hypoglycemic efficacy to glimepiride with drastically lower hypoglycemia incidencePMC. It exhibits no off-target activation on intestinal GPR43 or adipose GPR120, delivering outstanding target specificity without intestinal inflammation or lipid disorder side effects. During Phase 3 trials in 2013, multiple subjects presented elevated transaminases and drug-induced liver injury signals, leading Takeda to voluntarily terminate all clinical programs. Nevertheless, comprehensive preclinical, clinical efficacy and toxicology datasets establish TAK-875 as the core reference tool compound for GPR40 structural remodeling and hepatotoxicity mechanistic research.

For scientific research applications, TAK-875 covers three primary core scenarios. First, fundamental mechanistic research on GPR40 targets, applied to analyze receptor conformation, upstream and downstream signal cascade regulation, and experiments on pancreatic β-cell survival and proliferation. Second, screening of novel next-generation FFAR1 agonist lead compounds, acting as positive control to evaluate agonistic activity, selectivity and cellular toxicity of candidate molecules, guiding scaffold modification to mitigate liver toxicity liabilities. Third, extended cross-disciplinary neuro-metabolism research; published literatures confirm cerebral GPR40 expression, and TAK-875 modulates Aβ amyloid generation for exploration of intervention mechanisms against cognitive impairment in Alzheimer’s diseasepubmed-d.n.... It can also be combined with metformin and SGLT2 inhibitors in animal experiments to study multi-pathway synergistic hypoglycemic effects and comprehensive improvements in obesity and insulin resistance.

Regarding raw material supply and industrial value, the complete total synthetic route of TAK-875 is publicly available with mature controllable purification technology that stably removes biphenyl and benzofuran structural impurities, ensuring uniform batch activity and excellent experimental repeatability. Its solubility allows DMSO preparation of stock solutions for cell assays, while oral suspensions are suitable for long-term in vivo efficacy studies in rats and mice. Amid the global booming R&D wave of innovative FFAR1-targeted drugs, pharmaceutical manufacturers and research institutes continuously carry out structural derivatization and optimization to avoid the hepatic toxicity defects of original TAK-875, generating steadily rising demand for standard positive tool compounds. As a landmark compound in the history of GPR40 target development with complete clinical data and definite biological activity, TAK-875 maintains stable rigid market demand in cross-disciplinary research covering metabolic disease pharmacology, medicinal chemistry and neurodegenerative disorders, promising broad long-term research-oriented development prospects across the global pharmaceutical research industry.