Insulin and Oral Hypoglycaemic Agents Chemistry

Free pharmacy material

Insulin and Oral Hypoglycaemic Agents

INTRODUCTION

The pancreas contains at least four different types of endocrine cells, including A (alpha, glucagon-producing), B (beta, insulin-producing), D (delta, somatostatin-producing), and F (PP, pancreatic polypeptide-producing). Of these, the B cells are predominant. The most common pancreatic disease requiring pharmacologic therapy is diabetes mellitus, a deficiency of insulin production or effect.

Type-I diabetes occurs when the pancreas cannot produce insulin, a hormone essential for moving glucose from the blood into cells. It is an autoimmune disorder, in which the body makes antibodies that attack the insulin-producing cells in the pancreas. It is usually diagnosed in children and young adults, and was called juvenile diabetes. People with type-I diabetes must supply insulin by injection.

Type-II diabetes is the most common disorder. In this, either the body does not produce enough insulin or the cells ignore the insulin. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:

1. Body cells may be starved for energy.
2. Over time, high blood glucose levels may hurt the eyes, kidneys, nerves, or heart.

Gestational diabetes is a form of diabetes that appears only during pregnancy and occurs in women with no previous history of diabetes.

Some diabetic symptoms are frequent urination, excessive thirst, extreme hunger, unusual weight loss, increased fatigue, irritability, and blurred vision.

Insulin therapy suffers from several problems. Insulin alleviates the symptoms associated with the cause and, hence, the disease persists endlessly. Insulin is a proteinaceous substance capable of inducing an immune response in the patient. Hypersensitivity to insulin is common. Because of its nature it has to be injected, causing some discomfort to the patient. Insulin resistance is another problem.

INSULIN

Insulin, a pancreatic hormone, is a specific antidiabetic agent, especially for type-I diabetes. Human insulin is a double-chain protein with molecular mass around 6000 that contains 51 amino acids (chain A-21 amino acids, and chain B-30 amino acids), which are bound together by disulphide bridges.

20.2.1 Amino Acid Sequences (Structure) of Insulin

In the body, insulin is synthesised by β cells of Langerhans islets in the pancreas. In β cells, insulin is synthesised from the pro-insulin precursor molecule (pro-insulin consists of three domains: an amino-terminal B chain, a carboxy-terminal A chain, and a connecting peptide in the middle known as the C peptide) by the action of proteolytic enzymes, known as prohormone convertases (PC1 and PC2), as well as the exoprotease carboxypeptidase E. These modifications of pro-insulin remove the centre portion of the molecule (i.e., C peptide) from the C- and N-terminal ends of pro-insulin. The remaining polypeptides (51 amino acids in total), the B- and A-chains, are bound together by disulphide bonds.

Biosynthesis of Insulin.

Mechanism of Action of Insulin

The mechanism of the hypoglycaemic action of insulin has proposed that insulin acts by binding with specific receptors on the surface of the insulin-sensitive tissues such as skeletal muscle, cardiac muscle, fatty tissue, and leukocytes. Insulin lowers the sugar content in the blood by turning glucose into glycogen. Using insulin in diabetes mellitus leads to lower levels of sugar in the blood, and a build-up of glycogen in tissues.

The initial sources of insulin for clinical use in humans were cow, horse, pig, or fish pancreases. Insulin from these sources is effective in humans as it is nearly identical to human insulin (three amino acid difference in bovine insulin, one amino acid difference in porcine). Synthetic ‘human’ insulin is now manufactured for widespread clinical use by means of genetic engineering techniques using recombinant DNA technology, which the manufacturers claim reduces the presence of many impurities. Eli Lilly marketed the first such insulin, Humulin, in 1982.

Unlike many medicines, insulin cannot be taken orally. Like nearly all other proteins introduced into the gastrointestinal tract, it is reduced to fragments (even single amino acid components), where-upon all ‘insulin activity’ is lost. Insulin is usually taken as subcutaneous injections by single-use syringes with needles. In 2006 the U.S. Food and Drug Administration approved the use of Exubera, the first inhalable insulin. It has been withdrawn from the market by its maker as of 3Q 2007, due to lack of acceptance.

A great deal of research towards the development of more effective ways of treating the disease has led to the development of orally active agents. Oral hypoglycaemic agents or antidiabetic drugs are drugs that lower the level of glucose (sugar) in the blood.

ORAL HYPOGLYCAEMIC AGENTS CLASSIFICATION

. Sulphonyl ureas

Biguanides

	R	R1
Phenformin		H
Metformin	CH3—	CH3—
Buformin	CH3CH2CH2CH2—	H

3. Substituted Benzoic Acid Derivatives (Meglitinides)

. Thiazolidinediones (glitazones)

	R
Pioglitazone
Ciglitazone
Rosiglitazone

4. Miscellaneous drugs: Linogliride, Palmoxirate sodium

STRATEGY FOR CONTROLLING HYPERGLYCAEMIA

FIGURE 20.2 Mode of action of anti-diabetic drugs.

SULPHONYL UREAS

All members of this class differ by substitution at the para position on the benzene ring and at one nitrogen residue of the urea moiety. The discovery of this class was accidental. The compound 2-(p-aminobenzenesulphonamido)-5-isopropyl -thiadiazole (IPTD) was used in the treatment of typhoid fever in the early 1940s. However, many patients died from obscure causes while being treated with heavy doses of the drug. These deaths were eventually attributed to acute and prolonged hypoglycaemia. IPTD did not come to be used as hypoglycaemic agents because a second drug, carbutamide, was found to be an effective oral hypoglycaemic agent. Carbutamide was more active than IPTD and was the first sulphonylurea hypoglycaemic agent to be marketed.

Tolbutamide, chlorpropamide, and acetohexamide are first-generation sulphonyl ureas, while glibenclamide and glipizide are second generation.

Mechanism of action: Sulphonyl ureas bind to an ATP-dependent K+ (KATP) channel on the cell membrane of pancreatic β cells. This inhibits a tonic, hyperpolarizing outflux of potassium, which causes the electric potential over the membrane to become more positive. This depolarization opens voltage-gated Ca2+ channels. The rise in intracellular calcium leads to increased fusion of insulin granulae with the cell membrane, and, therefore, increased secretion of (pro)insulin.

There is some evidence that sulphonyl ureas also sensitize β cells to glucose, that they limit glucose production in the liver, that they decrease lipolysis (breakdown and release of fatty acids by adipose tissue), and that they decrease clearance of insulin by the liver.

General methods for preparation Sulphonyl ureas are accessible by many methods that have been developed for the preparation of simpler ureas—for example, treatment of 4-substituted sulphanilamide with substituted isocyanate affords sulphonyl ureas.

In the second method, 4-substituted sulphanilamide reacts with ethyl chloro formate followed by substituted amine.

Structure–activity relationship

1. The benzene ring should contain a substituent, preferably in the para position. The substituents like methyl, acetyl, amino, chloro, bromo, trifluoromethyl, and thiomethyl were found to enhance the antihyperglycaemic activity.
2. When the para position of benzene is substituted with arylcarboxamidoalky group (second-generation sulphonyl ureas like glibenclamide), the activity was found to be more enhanced. It is believed that this is because of a specific distance between the nitrogen atom of the substituent and the sulphonamide nitrogen atom.
3. The size of the group attached to the terminal nitrogen is crucial for activity. The group should also impart lipophilicity to the compound. N-Methyl and ethyl substituents show no activity, whereas N-propyl and higher homologues were found to be active, and the activity is lost when the N-substituent contains 12 or more carbons.

BIGUANIDES

In 1918, guanidine was found to lower blood glucose levels in animals. However, it was found to be toxic precluding its use in routine medicine. In the 1950s phenformin was found to have antidiabetic properties. Two other biguanides, metformin and buformin, were also introduced though not in the market.

Mechanism of action: Biguanides are antihyperglycaemic, not hypoglycaemic. The exact mode of action of biguanides is not fully elucidated. However, in hyperinsulinemia, biguanides can lower fasting levels of insulin in plasma. Their therapeutic uses derive from their tendency to reduce gluconeogenesis in the liver, and as a result, reduce the level of glucose in the blood. Biguanides also tend to make the cells of the body more willing to absorb glucose already present in the blood stream, and thereby reduce the level of glucose in the plasma.

Phenformin 2-(N-Phenethylcarbamimidoyl)guanidine

It is no longer widely available because it is known to induce lactic acidosis.

Synthesis

Condensation of 2-phenylethylamine with dicyanamide affords phenformin.

SUBSTITUTED BENZOIC ACID DERIVATIVES (MEGLITINIDES)

The meglitinides are similar in structure to sulphonyl ureas. The sulphonyl urea and meglitinide classes of oral hypoglycaemic drugs are referred to as endogenous insulin secretagogues because they induce the pancreatic release of endogenous insulin. Repaglinide is a new non-sulphonyl urea insulin secretagogue agent, the first available from the meglitinide class. Nateglinide, the newest member of the class, has recently become available. Unlike the commonly used sulphonyl ureas, the meglitinides have a very short onset of action and a short half-life. Some potential advantages of this class of agents include a greater decrease in postprandial glucose and a decreased risk of hypoglycaemia.

Mechanism of action: The mechanism of action of the meglitinides closely resembles that of the sulphonyl ureas. The meglitinides stimulate the release of insulin from the pancreatic beta cells. However, this action is mediated through a different binding site on the ‘sulphonyl urea receptor’ of the beta cell, and the drug has somewhat different characteristics when compared with the sulphonyl ureas. However, meglitinides do exert effects on potassium conductance. Like the sulphonyl ureas, the meglitinides have no direct effects on the circulating levels of plasma lipids.

Meglitinide N1-Phenethyl-5-chloro-2-methoxybenzamide

Synthesis

Reaction between 5-chloro-2-methoxybenzoic acid and phenylethylamine derivative affords the benzamide meglitinide.

Repaglinide   S(+)2-Ethoxy-4(2((3-methyl-1-(2-(1-piperidinyl)   phenyl)-butyl)amino)-2-oxoethyl)benzoic acid

Synthesis

Reaction between equimolar ratio of 1,4-dichloro-2-(1,2-dimethylpropyl)benzene and piperidine gives 1-[4-chloro-2-(1,2-dimethylpropyl)phenyl]piperidine. This, in turn, reacts with phenylacetic acid derivative in presence of thionyl chloride/carbonyl diimidazole to afford amide. Saponification of ester gives free acid, repaglinide.

THIAZOLIDINEDIONES

Thiazolidinediones are a new class of oral antidiabetic agents (commercially known as glitazones) that enhance insulin sensitivity in peripheral tissues. Rosiglitazone and pioglitazone are now available for clinical use, and are extremely potent in reducing peripheral insulin resistance. Because these agents do not increase insulin secretion, hypoglycaemia does not pose a risk when thiazolidinediones are taken as monotherapy. Besides their effect in lowering the blood glucose levels, both drugs also have notable effects on lipids. The current data show that pioglitazone has a minimal effect on low-density lipoprotein (LDL) cholesterol levels and a favourable effect on high-density lipoprotein (HDL) cholesterol and triglyceride levels. Rosiglitazone has a favourable effect on HDL cholesterol levels but a negative effect on LDL cholesterol levels. The thiazolidinediones are relatively safe in patients with impaired renal function because they are highly metabolised by the liver and excreted in the faeces.

Mechanism of action: These compounds act by binding to peroxisome proliferator-activated receptors (PPARs), a group of receptor molecules inside the cell nucleus, specificallyPPARγ (gamma). The normal ligands for these receptors are free fatty acids (FFAs) and eicosanoids. When activated, the receptor migrates to the DNA, activating transcription of a number of specific genes. By activating PPARγ: (a) insulin resistance is decreased; (b) adipocyte differentiation is modified; (c) VEGF-induced angiogenesis is inhibited; (d) leptin levels decrease (leading to an increased appetite); (e) levels of certain interleukins (e.g., IL-6) fall; and (f) adiponectin levels rise.

Ciglitazone 5-4-[(1-Methylcyclohexyl)methoxy]benzyl-1,3-thiazolidine-2,4-dione

Synthesis

Alkylation of 4-nitrophenol with 1-bromomethyl-1-methylcyclohexane gives 4-(1-methylcyclohexylmethoxy)nitrobenzene. Reduction of nitro group and diazotization of amino group followed by addition of methyl acrylate (Meerwein arylation) produce α-chlorinated ester. Reaction of this with thiourea probably proceeds through initial displacement of halogen by the nucleophilic sulphur; displacement of ethoxide by thiourea nitrogen leads, after bond reorganization, to the heterocycle ciglitazone.

Rosiglitazone 5-((4-(2-(Methyl-2-pyridinylamino) ethoxy)phenyl)methyl)- 2,4-thiazolidinedione

Synthesis

Alkylation of phenolic hydroxyl group with 2-iodoethyl acetate in presence of base gives phenoxy ester. Ester is interchanged to amide by reaction with methylamine, followed by reduction with boron trifluride to convert amide to amine. The secondary amine is further arylated by reaction with 2-fluoropyridine. Primary alcoholic group is oxidized to aldehyde, which in turn reacts with thiazolidine derivative to form benzylidene derivative; this on hydrogenation affords rosiglitazone.

A press release by GlaxoSmithKline in February 2007 noted that there is a greater incidence of fractures of the upper arms, hands, and feet in female diabetics given rosiglitazone compared with those given metformin.

MISCELLANEOUS DRUGS

Linogliride N4-(1-Methyltetrahydro-1H-2-pyrrolyliden)-4-phenyltetrahydro-2H-1,4-oxazine-4-carboximidamide

Synthesis

Condensation of phenyl isocyanate with 2-imino-1-methylpyrrolidine gives phenylthiourea derivative, which in turn undergoes S-alkylation with methyl iodide to give methyl mercapto derivative. An addition-elimination reaction with morpholine affords linogliride.

It works by an insulin secretagogue mechanism and stimulates the secretion of insulin in non-insulin-dependent patients.

NEWER DRUGS

Nateglinide 3-Phenyl-2-(4-isopropan-2-ylcyclohexyl) carbonylamino propanoic acid

It is a drug for the treatment of type-II diabetes. Nateglinide belongs to the meglitinide class of blood glucose-lowering drugs.

Pioglitazone 5-4-[2-(5-Ethyl-2-pyridyl)ethoxy]benzyl-1,3-thiazolidine-2,4-dione

It is used for the treatment of diabetes mellitus type-II (non-insulin-dependent diabetes mellitus, NIDDM) in monotherapy, but usually in combination with sulphonyl urea, metformin, or insulin.

Acarbose (2R,3R,4S,5R,6R)-5-[(2R,3R,4S,5R,6R)-5-[(2R,3R,4S,5R,6R)-3,4-dihydroxy-6-methyl-5-[[(1S, 4S,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]oxan-2-yl]oxy-3,4-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,4-triol

It is a carbohydrate drug and it inhibits enzymes (glycoside hydrolases) needed to digest carbohydrates—specifically, alpha-glucosidase enzymes in the brush border of the small intestines and pancreatic alpha-amylase. Pancreatic alpha-amylase hydrolyses complex starches to oligosaccharides in the lumen of the small intestine, whereas the membrane-bound intestinal alpha-glucosidases hydrolyse oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides in the small intestine. Inhibition of these enzyme systems reduces the rate of digestion of complex carbohydrates. Less glucose is absorbed because the carbohydrates are not broken down into glucose molecules. In diabetic patients, the short-term effect of these drug therapies is to decrease current blood glucose levels

Miglitol (2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl) piperidine-3,4,5-triol

It inhibits glycoside hydrolase enzymes called α-glucosidases. Since miglitol works by preventing digestion of carbohydrates, it lowers the degree of postprandial hyperglycaemia. It must be taken at the start of main meals to have maximal effect. Its effect will depend on the amount of non-monosaccharide carbohydrates in a person’s diet.