Biological Activity
as2034178 is a gpr40 agonist [1] with an hec50 value of 380 nm [2].gpr40 is a receptor of free fatty acid. it regulates glucose-dependent insulin secretion [1].as2034178 can improve glucose homeostasis and maintain or enhance islet beta cell functions [3]. as2034178 demonstrated highly and dose-dependently increase in intracellular ca2+ levels [1]. the maximum efficacy of the increase in ca2+ was nearly equal to that of an endogenous ligand of gpr40, namely linolenic acid. but the potency of as2034178 was much higher than that of linolenic acid. human gpr41-, gpr43-, gpr119-, and gpr120-overexpressing cho cells were developed to evaluate the increase of intracellular ca2+ concentration caused by as2034178. only gpr40-expressing cells showed increased intracellular ca2+. in pancreas b-cell–derived min6 cells, as2034178 dose-dependently and significantly induced insulin secretion only under high-glucose conditions (22.4 mm) [1].in ob/ob mice, chronic treatment with as2034178 significantly improved whole-body glucose metabolism, insulin, hba1c, and pancreatic insulin levels [2]. in normal mice, as2034178 at 0.3 to 10 mg/kg dose-dependently induced the suppression of plasma-glucose increases after oral administration with glucose, and the area decrease under the plasma glucose concentration-time curve was significant at doses over 1 mg/kg. after oral glucose administration, plasma insulin levels increased and at 5 minutes after glucose administration were dose-dependently and significantly increased at as2034178 dosages over 3 mg/kg [1].
References
[1]. tanaka h, yoshida s, oshima h, et al. chronic treatment with novel gpr40 agonists improve whole-body glucose metabolism based on the glucose-dependent insulin secretion[j]. journal of pharmacology and experimental therapeutics, 2013, 346(3): 443-452.
[2]. defossa e, wagner m. recent developments in the discovery of ffa1 receptor agonists as novel oral treatment for type 2 diabetes mellitus[j]. bioorganic & medicinal chemistry letters, 2014, 24(14): 2991-3000.
[3]. milligan g, alvarez-curto e, watterson kr, et al. characterizing pharmacological ligands to study the long-chain fatty acid receptors gpr40/ffa1 and gpr120/ffa4[j]. british journal of pharmacology, 2015, 172(13): 3254-3265.
