234 Medicinal Chemistry - II

CHAPTER
Antidiabetic Agents
16

16.1. ANTIDIABETIC AGENTS

16.1.1. Introduction
Diabetes mellitus is a group of metabolic diseases in which an individual has
high blood sugar level because the body either does not produce insulin in
sufficient amount , or the body cells do not respond to the in sulin formed.
Polyuria (frequent urination), polydipsia (increased thirst), and polyphagia
(increased hunger) are some typical symptoms caused by high blood sugar.

Diabetes may be of the following two types:

1) Diabetes Mellitus Type 1: It is caused due to the lack of insulin, thus insulin
should be injected to treat this condition.
2) Diabetes Mellitus Type 2: It is caused due to insulin resistance by cells. It is
the most common type of diabetes and can be treated using:
i) Agents increasing insulin secretion by the pancreas,
ii) Agents increasing the sensitivity of target organs to insulin, and
iii) Agents decreasing the rate at which glucose is absorbed from the GIT.

Anti-diabetic agents are used for treating diabetes mellitus by decreasing the
blood glucose levels. Some of these drugs are administered orally and termed
oral h ypoglycaemic or oral anti -hyperglycaemic agents ; however, insulin,
exenatide, and pramlinti de are the only anti-diabetic drugs that are injected.
Different classes of anti -diabetic drugs exist, and they are selected based on the
nature of diabetes, individual’s age and situation, and other factors.

16.1.2. Insulin
Paul Langerhans (a German medical student) in 1869 studied that the pancreas
has two different groups of cells, i.e., the acimer cells that secrete digestive
enzymes, and islets (cells clustered in islands ) that serve a second function.
Banting, Macleod, Bert, and Collip isolated insulin from bovine pancreas and
used it for treating diabetes mellitus.

Insulin is a hormone produced in pancreas and permits the body to utilise sugar
(glucose) from carbohydrates in the food. Insulin restricts the blood sugar level s
from getting too high (hyperglycaemia) or too low (hypoglycaemia). Insulin
occurs as a white or almost white coloured crystalline powder. It is faintly
soluble in water; soluble in dilute solution of mineral acids and with degradation
in solutions of alkali hydroxide; and almost insoluble in alcohol, chloroform, and
ether.
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Antidiabetic Agents (Chapter 16) 235

16.1.2.1. Synthesis
Significant quantity of insulin is synthesised in the pancreatic beta cells. The
insulin mRNA is translated as a single chain precursor known as pre-pro-
insulin, and removal of its signal peptide during insertion into the endoplasmic
reticulum produces pro-insulin.

Pro-insulin contains three domains, i.e., an amino-terminal B chain, a carboxy-

terminal A chain , and a C peptide (connecting peptide in the middle). Pro -
insulin, in the endoplasmic reticulum, is exposed to some specific endopeptidases
that excise the C peptide and generates the mature form of insulin. Insulin and
free C peptide are packaged in the Golgi into secretory granules accumulating
collect in the cytoplasm.
C - Peptide

SH SH

A Chain COO–

SH SH
Signal sequence
SH SH

–
H2N B.Chain
Preproinsulin

C - Peptide

S S
A Chain
S
S

S
S

B Chain
Proinsulin

S S
A Chain
S

S
S

B Chain
Insulin
Figure 16.1: Biosynthesis of Insulin
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236 Medicinal Chemistry - II

Insulin is secrete d from the pancreatic β-cells by exocytosis when these cells
are stimulated. After its release, the insulin diffuses into islet capillary blood.
C peptide is also secreted into bloodstream; however it is not biologically
active .

16.1.2.2. Mechanism of Action

Insulin produces its action throughout specific insulin receptors present on
cell membranes. Insulin binds to these receptors with high specificity and
affinity . The resultant insulin -receptor complex enters the cell and releases
insulin.

The receptors inversely vary with the plasma insulin concentrations. When
insulin concentration is high , these receptors are down -regulated (number
reduced), whereas in the presence of low insulin concentrations, these receptors
are u p-regulated (numbers increase). This leads to reduced and increased
responsiveness to insulin, respectively.

Apart from receptor numbers, reduced affinity of these receptors for insulin may
also contribute to insulin resistance. Thus in Type II diabetes , reduction in body
weight can restore responsiven ess to endogenous insulin by up -regulation and
increased affinity for insulin by these receptors.

The insulin receptor contains an extracellular α sub-unit (recognition site) and a β

sub-unit, spanning the cell membrane, and containing tyrosine kinase that
constitutes the second messenger system , which through a complex series of
phosphorylation leads to glucose transporter protein activation and e ntry of
glucose into the cell.

Internalisation of insulin receptor units inside the cell may help action of insulin
or result in lysosomal degradation of these receptors.

16.1.2.3. Uses
Insulin has the following uses:
1) It is used for controlling diabetes mellitus (uncontrollable by diet alone) or
for treating insulin dependent diabetes mellitus.
2) It is used for regulating carbohydrate metabolism.
3) It is used for treating hyperkalemia.
4) It is used for treating severe ketoacidosis or diabetic coma.

16.1.2.4. Insulin Preparations

Some common insulin preparations are given in the table 1:

* *
er 16) 237
Table 16.1: Insulin Preparations, Onset of Action, Peak Time, and Duration of Action
Preparations Effective
Onset of
Peak Time Duration of Comments
ric Names Trade Names Action
Action
Aspart NovoLog 5-10 minutes 1-3 hours 3-5 hours Eat within 5-10 minutes of injecting.
Lispro Humalog < 15 minutes 1  1 1 hours 2-4 hours Eat within 5-10 minutes of injecting.
2 2
Glulisine Apidra < 15 minutes 1 1
 1 hours 1 2
1 hours Take from 15  before to 20
2 2 2 meal. May only be mixed with NPH.
r Humulin R 1 2-3 hours 3-6 hours Humulin R is also made in U
Novolin R – 1 hours The onset is slower than U
2 is up to 24 hrs.
Humulin N 2-4 hours 4-10 hours 10-16 hours Roll vigorously to mix. Given once or twice
Novolin N daily.
Glargine Lantus 1 hour No peak 24 hours Do not put in the same syringe with any
other insulin. Usually given once daily.
r Levemir 1-2 hours No peak 6-23 hours, Do not put in the same syringe with any o
depending on dose insulin. May be given once or twice daily.
PH+ 30% Humulin 1 There are 2 peaks: 2-3 10-16 hours Roll vigorously to mix. Do not put in the
r 70/30 Novolin  1 hour hours and 4-10 hours same syringe with any other insulin.
2
70/30
spart Novolog Mix 5-10 minutes There are 2 peaks: 10-16 hours Eat within 5-10 minutes of injecting.
ine + 30% 70/30 1-3 hours and 4-10 hours Roll vigorously to mix. Do not put in the
same syringe with any other insul
ispro Humalog < 15 minutes There are 2 peaks: 1 1 10-16 hours Eat within 5-10 minutes of injecting.
1
ine + 50% 50/50 2 2 Roll vigorously to mix. Do not put in the
hours and 4-10 hours same syringe with any other insul
ispro Humalog < 15 minutes 1 1 10-16 hours Eat within 5-10 minutes of injecting.
ine + 25% Mix 75/25 There are 2 peaks: 1 Roll vigorously to mix. Do not put in the
2 2
same syringe with any other
hours and 4-10 hours
n may vary depending on the insulin dose, physical activity, site of injection, and temperature.

*
238 Medicinal Chemistry - II

16.2. ORAL HYPOGLYCAEMIC DRUGS

16.2.1. Introduction
Hypoglycaemic agents are used in the treatment of diabetes mellitus by lowering
the blood glucose levels. With the exceptions of insulin, exenatide, liraglutide
and pramlintide, all the other hypoglycaemic agents are administered orally and
are therefore known as oral hypoglycaemic agents or oral anti-hyperglycaemic
agents.

16.2.2. Classification
Hypoglycaemic agents are classified as follows:
1) Sulphonylureas:

Drugs R R1
Carbutamide
Tolbutamide
Chlorpropamide

Acetohexamide

Glibenclamide

Glipizide

2) Biguanides

Drugs R R1

Phenformin H

Metformin
Buformin H
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Antidiabetic Agents (Chapter 16) 239

3) Substituted Benzoic Acid Derivatives (Meglitinides)

4) Thiazolidindiones (Glitazones)

Drugs R

Pioglitazone

Ciglitazone

Rosiglitazone

5) Miscellaneous: Linogliride and Palmoxirate sodium

16.2.3. Sulphonylureas
Janbon and colleagues in 1942 accidentally observed that some sulphonamides
initiated hyperglycaemia in the experimental animals. Carbutamide was the first
sulphonylurea that was clinically used for treating the diabetes. Generally,
sulphonylureas are grouped into two generations or groups:
1) First Generation: Tolbutamide
2) Second Generation: Glibenclamide, Glimepiride, Glipizide, Gliclazide, and
*
Gliquidone. *
240 Medicinal Chemistry - II

All the sulphonylureas have similar actions, i.e., t hey decrease blood glucose
levels in type 2 diabetes.

16.2.3.1. Mechanism of Action

Sulphonylureas stimulate the secretion of insulin from the -cells of pancreas
without entering the cell ( figure 16.2). This occurs when glucose is not present .
Intact pancreatic -cells are required for the hypoglycaemic action of
sulphonylureas.

The -cells have sulphonylurea receptors linked to an AT Pase-sensitive K + ion

channel. As given in figure 16.2, inhibition of K + ion efflux causes
depolarisation of -cell membrane and opens the voltage-dependent Ca ++ ion
channels.

The kinases involved in exocytosis of secretory granules are activated by the

++
increased influx of Ca ions and their intracellular binding to calmodulin. Hence,
more insulin is released with increase in blood glucose level.

The potency order of sulphonylurea in binding to -cells approximates its

+
potency for stimulating insulin release and blocking the effect of K ions.
Sulphonylureas also act synergistically with insulin by raising insulin sensitivity
at a post-receptor level.
Parasympathetic nerves Sympathetic nerves and adrenaline
(On muscarinic receptors) (On 2 receptors)
–
GIT hormones +
Somatostatin
+ 1Cell
–
Glucose
+
Amino acids + -Cell –
Nutrients
Fatty acids +
+ 2Cell
+
– Glucagons
GIT Blood Insulin Pancreatic islet
Sulphonylureas
Figure 16.2: Endogenous Factors Regulating the Secretion of
Insulin by the -Cells of the Islets of Langerhans in the Pancreas

16.2.3.2. Structure-Activity Relationship

The benzene ring should contain a substituent in the para position. Substituents
like methyl, acetyl, amino, chloro, bromo, trifluoromethyl and thiomethyl
enhance the anti-hyperglycaemic activity.

Sulphonylureas
* *
Antidiabetic Agents (Chapter 16) 241

On substituting the para position of benzene with arylcarboxamidoalkyl group

(second generation sulphonylurea,such as glibenclamide), the anti-hyperglycaemic
is more enhanced. This happensbecause of a specific distance between the nitrogen
atom of the substituent and the sulphonamide nitrogen atom
.

Size of the group attached to the terminal nitrogen is essential for activity, and
should impart lipophilicity to the compound. N -Methyl and ethyl substituents do
not produce any activity, while N-propyl and higher homologues are active;
however, their activity is lost when the number of carbons in N-substituent is 12
or more.

16.2.3.3. Study of Individual Drugs

The following oral hypoglycaemic drugs are discussed below:
1) Tolbutamide,
2) Chlorpropamide,
3) Glipizide, and
4) Glimepiride.

16.2.3.4. Tolbutamide
Tolbutamide belongs to the class of sulph onylureas. It decreases the blood sugar
levels by affecting the pancreas to produce insulin and help the body to use
insulin effectively.

Tolbutamide

Synthesis

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242 Medicinal Chemistry - II

Mechanism of Action
Tolbutamide lowers the blood glucose level in individuals having Non-Insulin
Dependent Diabetes Mellitus (NIDDM) by directly stimulating insulin release
from the functioning pancreatic β-cells by a process that involves a
sulphonylurea receptor (receptor 1) on the beta cell.

Tolbutamide also inhibits the ATP -potassium channels on the β-cell membrane
and efflux of K + ions. This results in depolaris ation, influx of Ca ++ ions and their
binding to calmodulin, activation of kinase, and release of insulin -containing
granules by exocytosis.

Uses
1) It is used for controlling blood glucose in previously untreated NIDDM.
2) It is used in the treatment of diabetes which remains uncon trolled even after
proper diet.
3) It is used with metformin to control blood glucose level.
4) It is used as a substitute for other oral hypoglycemic agents.

16.2.3.5. Chlorpropamide
Chlorpropamide is an oral anti -hyperglycaemic agent used for treating NIDDM .
It comes under the sulphonylurea class of insulin secretagogues, which stimulate
the pancreatic β-cells to release insulin.

Chlorpropamide

Mechanism of Action
Chlorpropamide binds to ATP -sensitive potassium channels present on the
pancreatic cell surface, thus depolarises the membrane and reduces potassium
conductance.

This depolaris ation stimulates the influx of Ca ++ ions through volt age-sensitive
calcium channels. As a result, the intracellular concentration of Ca++ ions
increases, thus inducing the secretion or exocytosis of insulin.

Uses
1) It is taken with a proper diet and exercise program for controlling high blood
sugar in type 2 diabetic patients.
2) It can also be used as an adjunct to other diabetes drugs.

16.2.3.6. Glipizide
Glipizide is an oral medium -to-long acting anti -diabetic drug belonging to the
class of sulphonylurea. It is an oral hypoglycaemic agent that undergoes rapid
absorption and complete metabolism.
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Antidiabetic Agents (Chapter 16) 243

Glipizide

Mechanism of Action
Glipizide binds to ATP -sensitive potassium channels presen t on the pancreatic
cell surface, thus depolarises the membrane and reduces potassium conductance.
This depolarisation stimulates the influx of Ca ++ ions through voltage -sensitive
++
calcium channels. As a result, the intracellular concentration of Ca ions
increases, thus inducing the secretion or exocytosis of insulin.

Uses
It is use d as an adjunct to diet for controlling hyperglycaemia and its related
symptoms in patients having NIDDM (earlier NIDDM was known as maturity-
onset diabetes).

16.2.3.7. Glimepiride
Glimepiride is the first III generation sulphonyl urea. It is a highly potent
sulphonylurea having a long duration of action.

Glimepiride
Mechanism of Action
Glimepiride decreases blood glucose levels by stimulating insulin release from
the functioning pancreatic β-cells, and by increasing the sensitivity of peripheral
tissues to insulin. Glimepiride binds to ATP-sensitive potassium channels present
on the pancreatic cell surface, thus depolarises the membrane and reduces
potassium conductance.

This depolarisation stimulates the influx of Ca ++ ions through voltage -sensitive

++
calcium channels. As a result, the intracellular concentration of Ca ions
increases, thus inducing the secretion or exocytosis of insulin.

Uses
It is used with insulin for treating the non -insulin-dependent (type 2) diabetes
mellitus.
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244 Medicinal Chemistry - II

16.2.4. Biguanides
The generic formula of biguanides is:
R1  N  C  N  C  N  R2

H NH H NH H

Two commonly used biguanides are phenformin and metformin. They decrease
the blood glucose level in diabetic patien ts by potentiating the hyperglycaemic
action of insulin. They also increase the utilisation of glucose by muscles and
decrease the deflation of insulin.

16.2.4.1. Mechanism of Action

Biguanides act by:
1) Directly stimulating glycolysis in tissues,
2) Reducing hepatic and renal gluconeogenesis,
3) Delaying glucose absorption from the GIT by increasing the conversion of
glucose to lactate by enterocytes, and
4) Reducing the plasma levels of glucagon.

16.2.4.2. Study of Individual Drug - Metformin

Metformin is a biguanid e antihypertensive agent. It improves glycaemic control
by decreasing hepatic glucose production and glucose absorption, and also by
increasing insulin-mediated glucose uptake.

Mechanism of Action
Metformin reduces the blood glucose levels by decre asing hepatic glucose
production (gluconeogenesis), decreasing the intestinal absorption of glucose,
and increasing insulin sensitivity by increasing the glucose uptake and utilis ation
by the peripheral tissues.

Uses
1) It is used as an adjunct to diet and e xercise in NIDDM patients older than 18
years.
2) It can also be used for managing metabolic and reproductive abnormalities
related to polycystic ovary syndrome.
3) It can also be used with a sulphonylurea or insulin to improve glycaemic
control in adults.

16.2.5. Thiazolidinediones
Thiazolidinediones (TZDs or glitazones ) act by reducing the insulin resistance,
which is a common problem in many individuals having type 2 diabetes.
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Antidiabetic Agents (Chapter 16) 245

Thiazolidinediones allow insulin to effectively improve the blood glucose levels

by decreasing the body’s resistance to it. They also reduce the blood pressure and
improve lipid metabolism by increasing the levels of HDL (or good) cholesterol.

16.2.5.1. Mechanism of Action

Thiazolidinediones are selective agonists for nuclea r Peroxisome Proliferator -
Activated Receptor- (PPAR) that enhances the transcription of several insulin
responsive genes. Thiazolidinediones reverse insulin resistance by stimulating
GLUT4 expression and translocation, and also improve the entry of glucose into
muscles and fat. They also suppress h epatic gluconeogenesis. The insulin
sensitizing action of thiazolidinediones is due to the a ctivation of genes
regulating fatty acid metabolism and lipogenesis in adipose tissue.

16.2.5.2. Uses
Thiazolidinediones are used in individuals having type 2 diabetes mellitus. They
decrease blood glucose levels and HbA 1c without increasing the circulating
insulin. Some patients with low baseline insulin levels are non -responders.
Generally, they are used to supplement sulph onylureas/metformin in case of
insulin resistance. Thiazolidinediones are also used as monotherapy along with
diet and exercise in mild cases. They are also used to supplement insulin in
advanced cases.

16.2.5.3. Study of Individual Drugs

The following thiazolidinediones are discussed below:
1) Pioglitazone, and
2) Rosiglitazone.

16.2.5.4. Pioglitazone
Pioglitazone is used as an adjunct to diet, exercise, and other anti-diabetic drugs
to control type 2 diabetes mellitus.

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246 Medicinal Chemistry - II

Mechanism of Action
Pioglitazone is a selective agonist of Peroxisome Proliferator Activat ed
Receptor-γ (PPARγ) present in the target tissues (adipose tissue, skeletal muscle,
and liver) for insulin action. The PPAR-γ receptors on activation increase the
transcription of insulin -responsive genes that are involved in control ling
production, transport, and utilisation of glucose.

Thus, pioglitazone enhances tissue sensitivity to insulin and also reduces glucose
production via hepatic gluconeogenesis. In this way insulin resistance related to
type 2 diabetes mellitus is improved without increase in insulin secretion by the
pancreatic β cells.

Uses
It is used as an adjunct to diet and exercise for improving glycaemic control in
individuals having type 2 diabetes mellitus.

16.2.5.5. Rosiglitazone
Rosiglitazone is an anti -diabetic drug which not only acts on insulin resistance,
but also has anti-inflammatory effect; nuclear factor kappa -B (NFκB) levels fall
and inhibitor (IκB) levels increase in patients taking rosiglitazone.

Mechanism of Action
Rosiglitazone is a selective agonist of Peroxisome Proliferator Act ivated
Receptor-γ (PPARγ) present in the target tissues (adipose tissue, skeletal muscle,
and liver) for insulin action.

The PPAR -γ receptors on activation increase the transcription of insulin-

responsive genes that are involved in controlling production , transport, and
utilisation of glucose. Thus, rosiglitazone enhances tissue sensitivity to insulin.

Uses
It is used as an adjunct to diet and exercise for improving the glycaemic control
in individuals having type 2 diabetes mellitus.

16.2.6. Meglitinides
The structure of meglitinides is similar to that of sulphonylureas. The
sulphonylurea and meglitinide classes of oral hypoglycaemic drugs are termed as
endogenous insulin secretagogues as they induce the pancreatic release of
endogenous insulin.
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Antidiabetic Agents (Chapter 16) 247

Repaglinide is a new non -sulphonylurea insulin secretagogue, and the first

available. Nateglinide is another newest available meglitinide. Unl ike the
sulphonylureas, the meglitinides have a very short onset of action and a short
half-life. Some advantages of meglitinides are a greater decrease in post -
prandial glucose and a decreased risk of hypoglycaemia.

16.2.6.1. Mechanism of Action

The mechanism of action of meglitinides is also somewhat similar to that of
sulphonylureas. Meglitinides stimulate insulin release from the pancreatic β-cells,
and this action is mediated by a different binding site on the sulphonylurea
receptor of the β-cell. Meglitinides also act on potassium conductance. They do
not produce any direct effect on the circulating levels of plasma lipids.

16.2.6.2. Study of Individual Drugs

The following meglitinides are discussed below:
1) Repaglinide, and
2) Nateglinide.

16.2.6.3. Repaglinide
Repaglinide is used for treating NIDDM. It is an oral anti-hyperglycaemic drug
of meglitinide clas s having short-acting insulin secretagogues that bind to
pancreatic β-cells for stimulating insulin release.

Mechanism of Action
Repaglinide depends on the presence of functioning pancreatic β-cells and
glucose. It does not produce any effect on insulin re lease in the absence of
glucose; instead it potentiates the effect of extracellular glucose on ATP-sensitive
potassium channel and produces little effect on insulin levels between meals and
overnight.
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248 Medicinal Chemistry - II

Repaglinide more effectively reduces post-prandial blood glucose levels than

fasting b lood glucose levels and requires a longer duration of therapy ( one
month) before decreasing fasting blood glucose levels. The insulinotropic effects
of repaglinide are highest at intermediate g lucose levels (3 -10mmol/L) and it
does not increase insulin rel ease that is already stimulated by high glucose
concentrations (<15mmol/L). Repaglinide is selective for pancreatic β-cells and
does not affect skeletal or cardiac muscles or thyroid tissues.

Uses
It is used as an adjunct to diet and exercise for improving glycaemic regulation in
individuals having type 2 diabetes mellitus.

16.2.6.4. Nateglinide
Nateglinide is used for treating NIDDM. It is an oral anti-hyperglycaemic drug of
meglitinide class of short-acting insulin secretagogues that binds to pancreatic β-
cells of to stimulate insulin release.

Mechanism of Action
Nateglinide is an amino -acid derivative that lowers the blood glucose levels by
stimulating the release of insulin from pancreas. This action depends on the
functioning pancreatic β-cells. Nateglinide interacts with the ATP -sensitive
potassium channel present on pancreatic β-cells cell surface, thus depolarises the
membrane and reduces potassium conductance.

This depolarisation stimulates the influx of Ca ++ ions through voltage -sensitive

++
calcium channels. As a result, the intracellular concentration of Ca ions
increases, thus inducing the secretion or exocytosis of insulin.

Uses
It is used in conjunction with diet and exercise for treating non -insulin
dependent-diabetes mellitus.
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Antidiabetic Agents (Chapter 16) 249

16.2.7. -Glucosidase Inhibitors

The α-glucosidase inhibitors are oral anti-diabetic drugs. They are used for
treating type 2 diabetes mellitus by inhibiting the digestion of carbohydrates
starch and table sugar).

Generally, the carbohydrates are converted into simple sugars (monosaccharides)

that can be absorbed in the intestine s. Therefore, α-glucosidase inhibitor drugs
are used to decrease the effect of carbohydrates on blood sugar.

16.2.7.1. Mechanism of Action

The -glucosidase enzyme is found in the brush border of small intestine . This
enzyme is responsible for cleaving the dietary carbohydrate s and hence
enhancing their rapid absorption in the body.

Hence, any way which can inhibit this enzyme will leave less-dietary
carbohydrate available for absorption and thus, less available in the blood stream
after having a normal meal.

It is observed th at the usual inhibitory characteristic features of α-glucosidase

inhibitors are maximum for glycoamylase followed by sucrose, maltase , and
dextranase respectively.

16.2.7.2. Study of Individual Drugs

The following α-glucosidase inhibitors are discussed below:
1) Acarbose, and
2) Voglibose.

16.2.8. Acarbose
Acarbose is an inhibitor of α-glucosidase, which delays digestion and absorption
of carbohydrates in small intestine , and thus decreases the increase in blood -
glucose concentrations after a carbohydrate load.

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250 Medicinal Chemistry - II

Mechanism of Action
Acarbose reversibly bind s to pancreatic α-amylase and membrane -bound
intestinal α-glucoside hydrolases enzymes. The former enzyme inhibits the
hydrolysis of complex starches into oligosaccharides in the lumen of small
intestine; while the latter inhibits the hydrolysis of oligosaccharides,
trisaccharides, and disaccharides into glucose and other monosaccharides in the
brush border of small intestine.

Uses
It is used for treating type II diabetes in combination therapy as a second or third
line agent.

16.2.9. Voglibose
Voglibose is an α-glucosidase inhibito r. It is used for reducing post -prandial
blood glucose levels in individuals having diabetes mellitus.

Mechanism of Action
Voglibose is a competitive inhibitor of enzymes required for digestion of
carbohydrates. The most common enzyme is α-glucosidase present in the br ush
border of small intestines. The membrane-bound intestinal α-glucosidase enzyme
causes hydrolysis of oligosaccharides, tr isaccharides, and disaccharides, and
produces glucose and other monosaccharides in t he small intestine. Pancreatic α-
amylase causes hydrolysis of complex starches and produces oligosaccharides in
the lumen of small intestine.

When these enzymes are inhibited, the digestion rate of complex carbohydrates is
reduced. The carbohydrates are n ot broken down into glucose molecules, thus
less glucose is absorbed.

In diabetic patients, the short -term effect of voglibose decreases the blood
glucose levels, and the long -term effect is a small redu ction in haemoglobin-A1c
level.

Uses
1) It is used for treating diabetes.
2) Mainly, it is used for decreasing post -prandial blood glucose levels, hence
decreases the risk of macrovascular complications.
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Antidiabetic Agents (Chapter 16) 251

16.3. SUMMARY
The details given in the chapter can be summarised as follows:
1) Diabetes mellitus is a group of meta bolic diseases in which an individual
has high blood sugar level because the body either does not produce insulin
in sufficient amount, or the body cells do not respond to the insulin formed.
2) Anti-diabetic agents are used for treating diabetes mellitus by decreasing the
blood glucose levels.
3) Banting, Macleod, Bert, and Collip isolated insulin from bovine pancreas
and used it for treating diabetes mellitus.
4) Insulin is a hormone produced in pancreas and permits the body to utilise
sugar (glucose) from carbohydrates in the food.
5) Hypoglycaemic agents are used in the treatment of diabetes mellitus by
lowering the blood glucose levels.
6) Carbutamide was the first sulphonylurea that was clinically used for
treating the diabetes.
7) All the sulphonylureas have similar actions, i.e., they decrease blood
glucose levels in type 2 diabetes.
8) Tolbutamide belongs to the class of sulphonylureas.
9) Chlorpropamide is an oral anti -hyperglycaemic agent used for treating
NIDDM.
10) Glipizide is an oral medium -to-long a cting anti -diabetic drug belonging to
the class of sulphonylurea.
11) Glimepiride is the first III generation sulphonylurea.
12) Metformin is a biguanide antihypertensive agent.
13) Pioglitazone is used as an adjunct to diet, exercise, and other anti -diabetic
drugs to control type 2 diabetes mellitus.
14) Rosiglitazone is an anti -diabetic drug which not only acts on insulin
resistance, but also has anti -inflammatory effect; nuclear factor kappa -B
(NFκB) levels fall and inhibitor (IκB) levels increase in patients taking
rosiglitazone.
15) The sulphonylurea and meglitinide classes of oral hypoglycaemic drugs are
termed as endogenous insulin secretagogues as they induce the pancreatic
release of endogenous insulin.
16) Repaglinide is used for treating NIDDM. It is an oral anti -hyperglycaemic
drug of meglitinide class having short -acting insulin secretagogues that bind
to pancreatic β-cells for stimulating insulin release.
17) Acarbose is an inhibitor of α-glucosidase, which delays digestion and
absorption of carbohydrates in small intes tine, and thus decreases the
increase in blood-glucose concentrations after a carbohydrate load.
18) Voglibose is an α-glucosidase inhibitor.
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252 Medicinal Chemistry - II

16.4. EXERCISES

16.4.1. True or False

1) Diabetes mellitus is a group of metabolic diseases in which an individual has
low blood sugar level.
2) Anti-diabetic agents are used for treating diabetes mellitus by decreasing the blood
glucose levels.
3) Insulin is a hormone produced in pancreas and permits the body to utilise sugar
(glucose) from carbohydrates in the food.
4) Hypoglycaemic agents are used in the treatment of diabetes insipidus by lowering
the blood glucose levels.
5) Carbutamide was the first sulphonylurea that was clinically used for treating the
diabetes.
6) All the sulphonylureas have similar actions.
7) Chlorpropamide is an oral anti -hyperglycaemic agent used for treating type 1
diabetes.
8) Glimepiride is the first II generation sulphonylurea.

16.4.2. Fill in the Blanks

9) Tolbutamide belongs to the class of _____________.
10) _____________ is an oral medium-to-long acting anti-diabetic drug belonging to the
class of sulphonylurea.
11) Metformin is a ____________ antihypertensive agent.
12) _______________ is used as an adjunct to diet, exercise, and other anti -diabetic
drugs to control type 2 diabetes mellitus.
13) ____________ is an anti-diabetic drug which not only acts on insulin resistance, but
also has anti-inflammatory effect.
14) The sulphonylurea and meglitinide classes of oral hypoglycaemic drugs are termed
as ______________________ as they induce the pancreatic release of endogenous
insulin.
15) _____________- is used for treating NIDDM. It is an oral anti -hyperglycaemic drug
of meglitinide class having short -acting insulin secretagogues that bind to pancreatic
β-cells for stimulating insulin release.
16) _______ is an inhibitor of α-glucosidase, which delays digestion and absorption of
carbohydrates in small intestine, and thus decreases the increase in blood -glucose
concentrations after a carbohydrate load.
17) ________ is an α-glucosidase inhibitor.

Answers
1) False 2) True 3) True 4) False
5) True 6) True 7) False 8) False
9) Sulphonylurea 10) Glipizide 11) Biguanide 12) Pioglitazone
13) Rosiglitazone 14) Endogenous insulin secretagogues
15) Repaglinide 16) Acarbose 17) Voglibose
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Antidiabetic Agents (Chapter 16) 253

16.4.3. Very Short Answer Type Questions

1) Define antidiabetic agents.
2) What is insulin?
3) Give the uses of insulin.
4) What are oral hypoglycaemic agents?
5) Give the structure of tolbutamide.
6) What are biguanides?
7) What are thiazolidinediones?
8) Give the structure of rosiglitazone.

16.4.4. Short Answer Type Questions

1) Give the synthesis of insulin.
2) Write some common insulin preparation.
3) Give the classification of oral hypoglycaemic agents.
4) Write the SAR of sulphonylureas.
5) What is the mechanism of action and uses of thiazolidinediones?
6) Give the structure and mechanism of action of acarbose.

16.4.5. Long Answer Type Questions

1) Write a note on insulin in detail.
2) What are oral hypoglycaemic agents and give its classification and explain
sulphonylureas.
3) Write detailed notes on biguanides, meglitinides, and -glucosidase inhibitors.

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