Heterocyclic Ring Present In Glipizide

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Glimepiride (Amaryl)

Glipizide. Glipizide, 1 -cyclohexyl-3- [ [^-(2-(5-methyl-pyrazinecarboxamido)ethyl]phenyl]sulfonyl]urea (Glucotrol), is an off-white, odorless powder with a pKa of 5.9. It is insoluble in water and alcohols, but soluble in 0.1 N NaOH. Even though on a weight basis, it is approximately 100 times more potent than tolbutamide, the maximal hypoglycemic effects of these two agents are similar. It is rapidly absorbed on oral administration, with a serum half-life of 2 to 4 hours, whereas the hypoglycemic effects range from 12 to 24 hours. Metabolism of glipizide is generally through oxidation of the cyclohexane ring to the ^-hydroxy and m-hydroxy metabolites. A minor metabolite that occurs involves the ^-acetyl derivative, which results from the acetylation of the primary amine following hydrolysis of the amide system by amidase enzymes.

Glimepiride. Glimepiride, 1-[[^-[2-(3-ethyl-4-methyl-


3-(trans-4-methylcyclohexyl)urea (Amaryl), is very similar to glipizide with the exception of their heterocyclic rings. Instead of the pyrazine ring found in glipizide, glimepiride contains a pyrrolidine system. It is metabolized primarily through oxidation of the alkyl side chain of the pyrrolidine, with a minor metabolic route involving acetylation of the amine.

Gliclazide. Chemically, gliclazide, 1-(3-azabicy-clo[3.3.0]oct-3-yl)-3-^-tolylsulphonylurea (Diamicron), is very similar to tolbutamide, with the exception of the bi-cyclic heterocyclic ring found in gliclazide. The pyrrolidine increases its lipophilicity over that of tolbutamide, which increases its half-life. Even so, the ^-methyl is susceptible to the same oxidative metabolic fate as observed for tolbutamide, namely, it will be metabolized to a car-boxylic acid.

Gliclazide (Diamicron)

Gliclazide (Diamicron)


The metaglinides are nonsulfonylurea oral hypoglycemic agents used in the management of type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM). These agents tend to have a rapid onset and a short duration of action. Much like the sulfonylureas, these induce insulin release from functioning pancreatic [ cells. The mechanism of action for the metaglinides, however, differs from that of the sulfonylureas. The mechanism of action is through binding to specific receptors in the [ -cell membrane, leading to the closure of ATP-dependent K+ channels. The K+ channel blockade depolarizes the [-cell membrane, which in turn leads to Ca2+ influx, increased intracellular Ca2+, and stimulation of insulin secretion. Because of this different mechanism of action from the sulfonylureas, there are two major differences between these seemingly similar classes of agents. The first is that the metaglinides cause much faster insulin production than the sulfonylureas. As a result, the metaglinides should be taken during meals, as the pancreas will produce insulin in a much shorter period. The second difference is that the effects of the metaglinides do not last as long as the effects of the sulfonylureas. The effects of this class appear to last less than 1 hour, whereas sulfonyl-ureas continue to stimulate insulin production for several hours. One advantage of a short duration of action is that there is less risk of hypoglycemia.

Repaglinide. Repaglinide, (+)-2-ethoxy-4-[N-[3-methyl-1(S)-[2-(1-piperidinyl) phenyl]butyl]carbamoyl-methyl]ben-zoic acid (Prandin), represents a new class of nonsulfonylurea oral hypoglycemic agents. With a fast onset and a short duration of action, the medication should be taken with meals. It is oxidized by CYP 3A4, and the carboxylic acid may be conjugated to inactive compounds. Less than 0.2% is excreted unchanged by the kidney, which may be an advantage for elderly patients who are renally impaired. The most common side effect involves hypoglycemia, resulting in shakiness, headache, cold sweats, anxiety, and changes in mental state.


Nateglinide. Although nateglinide, N-(4-isopropylcy-clohexanecarbonyl)-d-phenylalanine (Starlix), belongs to the metaglinides, it is a phenylalanine derivative and represents a novel drug in the management of type 2 diabetes.

Nateglinide (Starlix)


The thiazolindiones represent a novel nonsulfonylurea class of hypoglycemic agents for the treatment of NIDDM. Much like the sulfonylureas, the use of these agents requires a functioning pancreas that can successfully secrete insulin from 3 cells. Although insulin may be released in normal levels from the cells, peripheral sensitivity to this hormone may be reduced or lacking. The thiazolidinediones are highly selective agonists for the peroxisome proliferator-activated receptor-y (PPARy), which is responsible for improving glycemic control, primarily through the improvement of insulin sensitivity in muscles and adipose tissue. In addition, they inhibit hepatic gluconeogenesis. These agents normalize glucose metabolism and reduce the amount of insulin needed to achieve glycemic control. They are only effective in the presence of insulin.

Rosiglitazone. Rosiglitazone, (±)-5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidine-dione (Avandia), is a white to off-white solid with pKa values of 6.8 and 6.1. Rosiglitazone is readily soluble in ethanol and a buffered aqueous solution with pH of 2.3; solubility decreases with increasing pH in the physiological range. The molecule has a single chiral center and is present as a racemate. Even so, the enantiomers are functionally indistinguishable because of rapid interconversion.

from the gastrointestinal tract. Also, they can decrease gluco-neogenesis while increasing glucose uptake by muscles and fat cells. These effects, in turn, lead to lower blood glucose levels. Unlike the sulfonylureas, these are not hypoglycemic agents but rather can act as antihyperglycemics. This difference in nomenclature is caused by the inability of these agents to stimulate the release of insulin from the pancreas. Often, metformin is coadministered with the nonsulfonylureas to improve the efficacy of those agents.

a-Glucosidase Inhibitors

The enzyme a-glucosidase is present in the brush border of the small intestine and is responsible for cleaving dietary carbohydrates and facilitating their absorption into the body. Inhibition of this enzyme allows less dietary carbohydrate to be available for absorption and, in turn, less available in the blood following a meal. The inhibitory properties of these agents are greatest for glycoamylase, followed by sucrose, maltase, and dextranase, respectively. Because these do not enhance insulin secretion when used as monotherapy, hypo-glycemia is generally not a concern when using these agents.

Acarbose. Acarbose, o-4,6-dideoxy-4-[[(1s,4r,5s,6s) 4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl]amino]a-d-glucopyranosyl-(1,4)-o-a-d-glucopyranosyl-(1,4)-d-glucose (Precose), is a naturally occurring oligosaccharide, which is obtained from the microorganism Actinoplanes utahensis. It is a white to off-white powder

Pioglitazone. Pioglitazone, (±)-5-[[4-[2-(5-ethyl-2-pyri-dinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione (Actos), is an odorless, white, crystalline powder that must be converted to a salt such as its hydrochloride before it will have any water solubility. Although the molecule contains one chiral center, the compound is used as the racemic mixture. This is primarily a result of the in vivo interconversion of the two enantiomers. Thus, there are no differences in the pharmacological activity of the two enantiomers.


Metformin. Metformin, N,N-dimethylimidodicarboni-midic diamide hydrochloride (Glucophage), is a bisguanidine. This class of agents is capable of reducing sugar absorption

that is soluble in water and has a pKa of 5.1. As one might expect, its affinity for a-glucosidase is based on it being a polysaccharide that the enzyme attempts to hydrolyze. This allows acarbose to act as a competitive inhibitor, which in turn reduces the intestinal absorption of starch, dextrin, and dissacharides.

Miglitol. Miglitol, 1-(2-hydroxyethyl)-2-(hydroxy-methylM2fl-(2a,30,4a,50)]-piperidine (Glyset), a des-oxynojirimycin derivative, is chemically known as 3,4,5-piperidinetriol. It is a white to pale yellow powder that is soluble in water, with a pKa of 5.9. In chemical structure, this agent is very similar to a sugar, with the heterocyclic nitrogen serving as an isosteric replacement of the sugar oxygen. This feature allows recognition by the a-glucosidase as a substrate. This results in competitive inhibition of the enzyme and delays complex carbohydrate absorption from the gastrointestinal tract.


Desiccated, defatted thyroid substance has been used for many years as replacement therapy in thyroid gland deficiencies. The efficacy of the whole gland is now known to depend on its thyroglobulin content. This is an iodine-containing globulin. Thyroxine was obtained as a crystalline derivative by Kendall79 of the Mayo Clinic in 1915. It showed much the same action as the whole thyroid substance. Later, thyroxine was synthesized by Harington and Barger80 in England. Later studies showed that an even more potent iodine-containing hormone existed, which is now known as triiodothyronine. Evidence now indicates that thyroxine may be the storage form of the hormone, whereas triiodothyronine is the circulating form. Another point of view is that in the blood, thyroxine is bound more firmly to the globulin fraction than is triiodothyronine, which can then enter the tissue cells.

Levothyroxine Sodium, USP. Levothyroxine sodium, 0-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-2-tyrosine monosodium salt, hydrate (Synthroid, Letter, Levoxine, Levoid), is the sodium salt of the levo isomer of thyroxine, which is an active physiological principle obtained from the thyroid gland of domesticated animals used for food by humans. It is also prepared synthetically. The salt is a light yellow, tasteless, odorless powder. It is hygroscopic but stable in dry air at room temperature. It is soluble in alkali hydroxides, 1:275 in alcohol, and 1:500 in water, to give a pH of about 8.9.

Levothyroxine sodium is used in replacement therapy of decreased thyroid function (hypothyroidism). In general, a dosage of 100 fig of levothyroxine sodium is clinically equivalent to 30 to 60 mg of thyroid USP.

Liothyronine Sodium, USP. Liothyronine sodium, O-(4-hydroxy-3-iodophenyl)-3,5-diiodo-l-thyroxine monosodium salt (Cytomel), is the sodium salt of l-3,3',5-triiodothyronine. It occurs as a light tan, odorless, crystalline powder, which is slightly soluble in water or alcohol and has a specific rotation of +18 to 22 degrees in a mixture of diluted HCl and alcohol.

Liothyronine sodium occurs in vivo together with levothyroxine sodium; it has the same qualitative activities as thyroxine but is more active. It is absorbed readily from the gastrointestinal tract, is cleared rapidly from the bloodstream, and is bound more loosely to plasma proteins than is thyroxine, probably because of the less acidic phenolic hy-droxyl group.

Its uses are the same as those of levothyroxine sodium, including treatment of metabolic insufficiency, male infertility, and certain gynecological disorders.

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  • Maximilian
    Which basic ring is present in glipizide?
    3 years ago

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