Uses
AS 2034178 is used in the synthetic preparation of quinolines and related compounds as GPR40 agonists, some of which are potentially useful in the treatment of diabetes.
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.
