MB05032

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Background

MB05032 is a potent and selective GNG inhibitor targeted the AMP binding site of fructose 1,6-bisphosphatase (FBPase) with an IC50 value of 16 nM [1].Gluconeogenesis (GNG) is a metabolic pathway which could result in the generation of glucose from certain non-carbohydratecarbon substrates.
In vitro: MB06322 inhibited glucose synthesis by human hepatocytes over a narrow concentration range with full inhibition achieved at 1 μM in a concentration-dependent manner [2]. MB05032 inhibited human liver FBPase with a potency (IC50 of 16 ± 1.5 nM) significantly greater than the natural inhibitor, AMP (IC50 of 1 μM), and the most well characterized AMP mimetic, ZMP (IC50of 12 ± 1.4 μM). MB05032 inhibited rat FBPase 3-fold weaker (IC50 of 61 ± 4 nM) than human FBPase, whereas AMP was 20-fold weaker as an inhibitor [1]. In islet β-cells,inhibition of FBPase activity by MB05032 led to a significant increase of their glucose utilization and cellular ATP to ADP ratios and consequently enhanced GSIS in vitro [2].
In vivo: In male ZDF rats, oral administration of MB06322 resulted in dose-dependent inhibition of [14C]bicarbonate incorporation into glucose. Maximal GNG inhibition (≈80%) is achieved at 100–300 mg/kg MB06322. In MB06322-treated rats, intermediates upstream of FBPase WERE elevated 1.5- to 3.1-fold relative to vehicle-treated mice. MB06322 treatment also resulted in elevated lactate levels (79%) only in aged ZDF rats. [2]. Oral administration of MB06322 to young (8–9 weeks old) ZDF rats with mild diabetes (basal insulin levels of 7.7 ± 0.7 ng/ml) and aged (12–13 weeks) ZDF rats with overt diabetes (basal insulin levels of 0.65 ± 0.16 ng/ml) lowered the level of glucose in a dose-dependent manner [1]. The dose–dependent response is relatively steep, with 6–10 mg/kg and 30–100 mg/kg being the approximate doses associated with minimal and maximal activity, respectively. After drug administration 2.5–5 h, glucose lowering occurs rapidly with maximal effects [1].

[1] Erion M D, van Poelje P D, Dang Q, et al. MB06322 (CS-917): A potent and selective inhibitor of fructose 1, 6-bisphosphatase for controlling gluconeogenesis in type 2 diabetes[J]. Proceedings of the National Academy of Sciences, 2005, 102(22): 7970-7975.
[2] Zhang Y, Xie Z, Zhou G, et al. Fructose-1, 6-bisphosphatase regulates glucose-stimulated insulin secretion of mouse pancreatic β-cells[J]. Endocrinology, 2010, 151(10): 4688-4695.