Biological Activity
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].
target
IC50: 16 nM (Human Liver FBPase)
References
[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.
