261365-11-1

Basic information

• Product Name: MB-05032
• Synonyms: MB-05032;2-Amino-5-isobutyl-4-[5-phosphono-2-furanyl]thiazole;[5-(2-Amino-5-isobutyl-1,3-thiazol-4-yl)-2-furyl]phosphonic acid
• CAS NO: 261365-11-1
• Molecular Formula: C₁₁H₁₅N₂O₄PS
• Molecular Weight: 302.286561
• Mol File: 261365-11-1.mol

Chemical Properties

• Boiling Point: 576.7±60.0 °C(Predicted)
• Appearance: /
• Density: 1.47±0.1 g/cm3(Predicted)
• Solubility: Soluble in DMSO
• PKA: 0.98±0.10(Predicted)
• CAS DataBase Reference: MB-05032(CAS DataBase Reference)
• NIST Chemistry Reference: MB-05032(261365-11-1)
• EPA Substance Registry System: MB-05032(261365-11-1)

Safety Data

• Hazardous Substances Data: 261365-11-1(Hazardous Substances Data)

Usage

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].

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.

Upstream product

• 261372-76-3 2-amino-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole 
• 213125-12-3 [5-(4-methylpentanoyl)furan-2-yl]phosphonic acid diethyl ester 
• 347869-08-3 [5-(2-bromo-4-methylpentanoyl)furan-2-yl]phosphonic acid diethyl ester 
• 646-07-1 4-Methylpentanoic acid 
• 78072-59-0 1-(furan-2-yl)-4-methylpentan-1-one 

Downstream Products

• 1000608-23-0 2-amino-4-[2-(5-(O-phenyl)-(N-((S)-1-ethoxycarbonyl)ethyl)phosphonamido)furanyl]-5-isobutylthiazole hydrochloride 

Relevant articles and documents

Preparation method of Managlinat Dialanetil

The invention discloses a preparation method of Managlinat Dialanetil. The method comprises the following steps: 1, adding ethylene glycol and triethyl orthoformate to 2-(4-methylvaleryl)-furan, and carrying out a ketalization reaction under the action of an acid catalyst to obtain a ketal mixture; 2, carrying out a phosphorylation reaction on the ketal mixture and diethyl chlorophosphate, and carrying out a deprotection reaction after the phosphorylation reaction is completed to obtain a phosphoryl lipid intermediate; 3, carrying out a bromination reaction on the phosphoryl lipid intermediate to obtain a bromide; 4, carrying out a ring closure reaction on the bromide and thiourea to obtain a thiazole intermediate; and 5, carrying out a one-pot reaction on the thiazole intermediate, TMSBr and L-alanine ethyl ester hydrochloride under the action of triphenylphosphine and dithiodipyridine, and carrying out post-treatment after the reaction is completed to obtain the Managlinat Dialanetil. The preparation method simplifies the reaction operation through optimizing step 1 and step 5, reduces the dosage of reagents and improves the reaction yield.

Discovery of potent and specific fructose-1,6-bisphosphatase inhibitors and a series of orally-bioavailable phosphoramidase-sensitive prodrugs for the treatment of type 2 diabetes

Excessive glucose production by the liver coupled with decreased glucose uptake and metabolism by muscle, fat, and liver results in chronically elevated blood glucose levels in patients with type 2 diabetes. Efforts to treat diabetes by reducing glucose production have largely focused on the gluconeogenesis pathway and rate-limiting enzymes within this pathway such as fructose-1,6-bisphosphatase (FBPase). The first potent FBPase inhibitors were identified using a structure-guided drug design strategy (Erion, M. D.; et al. J. Am. Chem. Soc. 2007, 129, 15480-15490) but proved difficult to deliver orally. Herein, we report the synthesis and characterization of a series of orally bioavailable FBPase inhibitors identified following the combined discoveries of a low molecular weight inhibitor series with increased potency and a phosphonate prodrug class suitable for their oral delivery. The lead inhibitor, 10A, was designed with the aid of X-ray crystallography and molecular modeling to bind to the allosteric AMP binding site of FBPase. High potency (IC50 = 16 nM) and FBPase specificity were achieved by linking a 2-aminothiazole with a phosphonic acid. Free-energy perturbation calculations provided insight into the factors that contributed to the high binding affinity. 10A and standard phosphonate prodrugs of 10A exhibited poor oral bioavailability (0.2-11%). Improved oral bioavailability (22-47%) was achieved using phosphonate diamides that convert to the corresponding phosphonic acid by sequential action of an esterase and a phosphoramidase. Oral administration of the lead prodrug, MB06322 (30, CS-917), to Zucker Diabetic Fatty rats led to dose-dependent inhibition of gluconeogenesis and endogenous glucose production and consequently to significant blood glucose reduction.

Novel phosphorus-containing prodrug

Novel cyclic phosphoramidate prodrugs of parent drugs MH of formula I their use in delivery of drugs to the liver, their use in enhancing oral bioavailability, and their method of preparation are described.