Description
Miglitol was introduced in Germany as an auxiliary treatment
for non-insulin dependent diabetes (NIDDM). A simple two-step synthesis of
Miglitol consists of converting 6-desoxy-6-aminosorbose into desoxynojirimycin
by reductive cyclization, then selectively hydroxyethylating the cyclic nitrogen.
Miglitol is a short-acting intestinal alpha-D-glucosidase inhibitor, reducing
postprandial glucose excursions by helping to delay absorption of complex
carbohydrates. Acarbose and voglibose are the previous compounds marketed
in this class. At low doses, orally administered miglitol was shown to be rapidly
and completely absorbed then removed by renal excretion.
Chemical Properties
white to light yellow crystal powde
Originator
Bayer (Germany)
Uses
An inhibitor of alpha-glucosidases.
Uses
A potent α-glucosidase inhibitor. A new antidiabetic drug.
Production Methods
Miglitol requires 1-deoxynojirimycin as a precursor which can be obtained via three different routes: extraction from plants such as the mulberry tree, fermentation using various bacterial strains, and a complete chemical synthesis. Industrially feasible production of miglitol was, however, restricted by expensive purification steps or low yields. Hence, a new approach was adopted in which a combination of biochemical and chemical synthesis was employed (Schedel, 2000). In this approach, D-glucose is converted to 1-amino-D-sorbitol by reduction with suitable amines and hydrogen, with nickel as catalyst, and then further reaction of products with appropriate acid esters (Kinast and Schedel, 1979). The oxidation of 1-amino-D-sorbitol to 6-amino-L-sorbose is then carried out in a fermenter using Gluconobacter oxydans grown at temperatures between 20 and 45 C, preferably at roomtemperature and maintaining thepHbetween 2.0 and 9.0. At this pH, 6-amino-L-sorbose is present in the medium as piperidinose, which is reduced to 1-desoxy-nojirimycin in the presence of inert solvents and by choosing the appropriate pH. After this, miglitol is obtained by first centrifuging the biomass followed by clarification using active charcoal. Next, separation of catalyst, evaporation of solvents, and isolation of any remaining salts in the medium is carried out (Kinast and Schedel, 1979). An important modification necessary in this process is the addition of protection groups before feeding 1-amino-D-sorbitol to the G. oxydans cultures and their subsequent removal before the ring-closure reaction. This is necessary since1-amino-D-sorbitol is readily oxidized by G. oxydans strains to form 3-hydroxy-2-hydroxymethyl-pyridine at near-neutral pH as a result of spontaneous ring closure (Schedel, 2000).
Definition
ChEBI: Miglitol is a member of piperidines.
Indications
Miglitol [Glyset] is the second alpha-glucosidase inhibitor approved in the United States. Like acarbose, miglitol delays conversion of oligosaccharides and complex carbohydrates to glucose and other monosaccharides, and thereby reduces the postprandial rise in blood glucose. In clinical trials, the drug was especially effective among Latinos and African Americans. Hypoglycemia does not occur with miglitol monotherapy, but may occur if the drug is combined with insulin or a sulfonylurea. Like acarbose, miglitol causes flatulence, abdominal discomfort, and other GI effects. In contrast to acarbose, miglitol has not been associated with liver dysfunction. As with acarbose therapy, oral sucrose cannot be used to treat hypoglycemia. Rather, oral glucose must be given. Miglitol is available in 25-, 50-, and 100-mg tablets. The initial dosage is 25 mg 3 times daily before meals. The maintenance dosage is 50 or 100 mg 3 times a day.
Manufacturing Process
50 g (0.23 mole) of 6-amino-6-desoxy-L-sorbose hydrochloride were dissolved in 500 ml of distilled water, and the solution was added in the course of onehour to a solution of 11.2 g of dimethylaminoborane in 500 ml of distilledwater, whilst stirring at a temperature of 50°C. The mixture was stirred forone hour at room temperature and one hour at 50°C, 5 ml of triethylaminewere added to it, and it was then poured over a column containing 800 ml ofstrongly basic ion exchanger ("Lewatit" MP 500 OH--form). The exchangerwas washed with distilled water, and the runnings collected were concentratedto a syrup on a rotary evaporator. The concentrated syrup was crystallised at50°C on addition of a large amount of ethanol. The suspension of crystals wascooled and filtered off under suction, and the crystalline product was dried ina vacuum drying cabinet. Yield: 30 g, 80% of theory. MP: 192°-193°C.
25 g (0.115 mole) 1,5-didesoxy-1,5-imino-D-glucitol of 6-amino-6-desoxy-L-sorbose hydrochloride were dissolved in 200 ml of distilled water, and thesolution was added at 5°C to a mixture of 4.8 g of NaBH4, 250 ml ofethanol/water 1:1 and 16.2 ml of triethylamine, whilst stirring. The mixturewas further stirred for one hour at room temperature and one hour at 50°C.,and the reaction mixture was poured over a column containing 400 ml ofstrongly basic ion exchanger ("Lewatit" MP 500 OH-form). The exchanger waswashed with distilled water, and the eluate collected was concentrated to asyrup in a rotary evaporator. Th syrup was taken up with 200 ml of distilledwater, and the mixture was poured over a column containing 400 ml of acidion exchanger ("Lewatit" S 100 H+-form). The column was rinsed withdistilled water, and the product was eluted with 10% strength ammonia water.The runnings, rendered alkaline with ammonia, were collected and wereconcentrated to a syrup in a rotary evaporator. The syrup was crystallized,whilst warm, with a large amount of ethanol, and the suspension of crystalswas cooled and is filtered off under suction, and the crystalline product wasdried in a vacuum drying cabinet. Yield of 1,5-dideoxy-1,5-((2-hydroxyethyl)imino)-D-glucitol 14 g, 74% of theory. MP: 192°-193°C.
brand name
Glyset (Pharmacia & Upjohn);Diastabol.
Therapeutic Function
Glucosidase inhibitor
General Description
Miglitol, 1-(2-hydroxyethyl)-2-(hydroxymethyl)-[2R-(2α,3β ,4α,5β)]-piperidine (Glyset), a desoxynojirimycinderivative, is chemically known as 3,4,5-piperidinetriol. It is a white to pale yellow powder that issoluble in water, with a pKa of 5.9. In chemical structure,this agent is very similar to a sugar, with the heterocyclic nitrogenserving as an isosteric replacement of the sugar oxygen.This feature allows recognition by the -glucosidase asa substrate. This results in competitive inhibition of the enzymeand delays complex carbohydrate absorption from thegastrointestinal tract.
General Description
Miglitol is (2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)-3,4,5-piperidinetriol, or N-hydroxyethyl-1-deoxynorjirimycin. The drug is available as 25-, 50-, and100-mg tablets (Glyset), for administration 25 to 100 mgt.i.d. with meals. In contrast to acarbose, miglitol is highlyabsorbed from a 25-mg oral dose, although absorption is reportedto be saturable, and accordingly less complete athigher doses. Binding to plasma proteins is minimal, andthe volume of distribution (0.18 L/kg, corresponding to12–13 L in a 70-kg adult) is characteristic of compoundsdistributed only to blood and extracellular fluids. Practicallyno systemic biotransformation of miglitol occurs in humans;essentially 100% of an orally administered dose is excretedintact in urine.
Mechanism of action
The mechanism of action of miglitol is very similar to that of acarbose; it has strong binding affinity to digestive enzymes and, as a result, prevents these enzymes from binding to complex carbohydrates thereby delaying glucose absorption and resulting in reduction in postprandial plasma levels. The difference to note is that miglitol is a competitive inhibitor of digestive enzymes as a substitute for glucose, whereas acarbose functions as a substitute for the starch and oligosaccharides. Miglitol shows inhibitory action toward almost all the digestive enzymes present in the brush border of small intestine with the following ranking order: sucrase > glucoamylase > isomaltase > lactase > trehalase, and some inhibitory activity toward a-amylase (Lembcke et al., 1985; Scott and Spencer, 2000).
Both acarbose and voglibose are not absorbed in the upper section of upper intestine. Miglitol, however, is almost completely absorbed in the small intestine (Scott and Spencer, 2000; Tan, 1997). The absorption of miglitol is dose dependent, with 25 mg of miglitol rapidly and completely absorbed. However, higher doses of up to 100 mg do not get fully absorbed, and 95% of miglitol is excreted out of the system via urine and feces almost unchanged. The amount excreted depends upon the systemic absorption, and therefore on the dose administered. With the lowest dose of 25 mg, almost 95% excretion is achieved, but with higher dosages this amount drops. The half-life of miglitol in healthy volunteers is 2–3 h for a less potent dose of 50 mg (Ahr et al., 1997; Campbell et al., 2000; Scott and Spencer, 2000).
Clinical Use
One of the widely used a-glucosidase inhibitors for treatment of Type II diabetes is miglitol (C8H17NO5; IUPAC name (2R,3R,4R,5S)-1-(2-hydroxyethyl)- 2-(hydroxymethyl)piperidine-3,4,5-triol; molecular weight 207.2). Miglitol is a second-generation a-glucosidase inhibitor derived from 1-deoxynojirimycin, which is yet another a-glucosidase inhibitor and is structurally similar to glucose (Tan, 1997). It is a white to pale yellow powder and is soluble in water (Campbell et al., 2000). Miglitol was approved by the U.S. Food and Drug Administration (FDA) in 1996 as an additional therapy to diet alone therapy or diet plus sulfonylurea therapy in patients with Type II diabetes. Miglitol’s story begins with the successful attempts for identifying new compounds with inhibitory properties, which initially resulted in the discovery of nojirimycin, deoxynojirimycin, and their derivatives from various Bacillus and Streptomyces strains (Schmidt et al., 1979). During initial attempts, 1-deoxynojirimycin was successfully obtained (Schmidt et al., 1979); however, its N-hydroxyethyl analog (miglitol) later proved to possess better inhibitory activities. It is currently being manufactured by Bayer AG under the trade name of Glysetò in USA and as Diastabolò in Europe. Miglitol is considered to be a good choice for the therapy of patients who have the relative risk of developing hypoglycemia, weight gain, or lactic acidosis (Campbell et al., 2000). It is observed to have the same efficacy as acarbose at lesser dosages (50 and 100 mg tid). Miglitol therapy provides better reduction on fasting and postprandial plasma glucose levels in patients in comparison with sulfonylureas (Scott and Spencer, 2000), whereas voglibose, another a-glucosidase inhibitor, could achieve reduction only for postprandial glucose levels.
Synthesis
1-Deoxynojirimycin and its N-substituted analog N-hydroxyethyl-1- deoxynojirimycin (miglitol) are strong inhibitors of α-glucosidases and are used for the treatment of non-insulin-dependent diabetes (Campbell et al., 2000). The industrial production of these compounds follows a combined biotechnological- chemical synthesis, whereby G. oxydans plays a key-role in the oxidation of 1-aminosorbitol derivatives. As Gluconobacter cannot grow on aminopolyols, whole resting cells (grown on sorbitol) have to be used for this biotransformation process.
SYNTHESIS OF 1-DEOXYNOJIRIMYCIN AND MIGLITOL
References
1) Lee et al. (2002), The effects of miglitol on glucagon-like peptide-1 secretion and appetite sensations in obese type 2 diabetics; Diabetes Obes. Metab., 4 329
2) Nomura et al. (2011), Effects of miglitol in platelet-derived microparticle, adiponectin, and selectin level in patients with type 2 diabetes mellitus; Int. J. Gen. Med., 4 539
3) Yokoyama et al. (2007), Miglitol increases the adiponectin level and decreases urinary albumin excretion in patients with type 2 diabetes mellitus; Metabolism, 56 1458
