Introduction Formation of blood cells (Hemopoiesis/hematopoiesis)

1. Chapter 3
Oral Hypoglycemic Agents

2. Classification of Diabetes mellitus
There are two main types of diabetes
Type 1 (requiring insulin for survival) and
 Type 2 (may or may not require insulin for
metabolic control)
It is recommended that the terms
Insulin-dependent diabetes mellitus (IDDM)
for type 1 and
Non-insulin-dependent diabetes mellitus
(NIDDM)for type 2
No longer be used

3. Antidiabetic Drugs
 Antidiabetic drug includes insulin & oral hypoglycemic agents
 Insulin
 Can be commercially prepared for treatment of type I, gestational &
some type II diabetes
 The first insulin which was made available commercially for clinical use
was amorphous insulin
 Purification of amorphous insulin led to crystalline insulin
Which is now commonly called regular insulin
 Insulin injection, USP, is made from zinc insulin crystal
 Sometimes regular insulin solutions have been prepared at a pH of
2.8 – 3.5
If the pH were increased above the acidic range, particles will be
formed
 Neutral insulin solutions have greater stability than acidic solutions
 Neutral solutions maintain nearly full potency when stored up to
18 months at 5o
C & 25o
C

4. Oral hypoglycemic agents
 The oral hypoglycemic agents
 Are used to treat patients with type 2 diabetes that is not
controlled by diet and exercise alone
 Are not effective for treating type 1 diabetes
 May also be used with insulin in the management of some
patients with diabetes mellitus
Use of an oral antidiabetic drug with insulin
May decrease the insulin dosage in some individuals
 The patient most likely to respond well to oral
hypoglycemic agents is one who develops diabetes after
age 40 and has had diabetes less than 5 years
 Patients with long-standing disease may require a
combination of a
 Hypoglycemic drug and insulin to control their
hyperglycemia

5. Oral hypoglycemic agents cont.
Oral hypoglycemic drugs act in one or more
of the following:
Stimulating the release of insulin by the
pancreas (Insulinotropic agents )
Slowing the absorption of glucose from
the intestines
Decreasing glucose synthesis and
release by the liver
Making cells more sensitive to insulin
(e.g., muscle and liver)

6. CURRENT DRUGS ON THE MARKET
Drugs currently available for
treatment of hyperglycemia
associated with diabetes mellitus
fall into four classes:
 Insulin and its analogs
 Insulinotropic agents
 Insulin-sensitizing agents
 Alpha-Glucosidase inhibitors

7. CURRENT DRUGS ON THE MARKET cont.
Types of oral antidiabetic drugs are currently in use:
 Sulfonylureas (e.g. glyburide/ Glibenclamide/,
glimepiride)
 Meglitinides/Glinides (e.g. nateglinide, repaglinide)
 Biguanides (e.g. metformin)
 Alpha (α)-glucosidase inhibitors (e.g. acarbose,
miglitol)
 Thiazolidinediones (e.g. pioglitazone, rosiglitazone)

8. Insulinotropic agents
 Insulinotropic agents are agents that directly stimulate
the release of insulin from pancreatic β-cells
 The drugs in this class are often divided into the
subclasses:
Sulfonylureas and glinides
These compounds are structurally related and
share a common mechanism of action
Sulfonylureas
It appear to lower blood glucose by stimulating
the beta cells of the pancreas to release insulin
They are not effective
If the beta cells of the pancreas are unable to
release a sufficient amount of insulin to meet
the individual’s needs

9. Sulfonylureas
 The sulfonylureas are divided into different generations:
 The first generation sulfonylureas
Includes tolbutamide, acetohexamide, tolazamide, and
chlorpropamide
Are not commonly used today because they have a
Long duration of action and
Higher incidence of adverse reactions, and
 Are more likely to react with other drugs
 The second generation sulfonylureas
 Includes glyburide (glibenclamide), glipizide, gliclazide,
They are the more commonly used sulfonylureas
 Third generation
Glimepiride
Some classify glimepiride as second-generation, while others
classify it as third-generation
 Fourth generation (light-dependent)
JB253

10. Sulfonylureas cont.
The mechanisms of action of the sulfonylureas include:
Stimulation of insulin release from the β-cells of the
pancreas
Reduction of serum glucagon levels and
Increased binding of insulin to target tissues and
receptors
They act by closing membrane-bound ATP-sensitive
potassium (KATP) channels on the β-cell
Causing depolarization and the opening of voltage-
gated calcium channels.
The resulting influx of Ca2+
triggers exocytosis of
insulin

11. Sulfonylureas cont.
These drugs are contraindicated in patients with hepatic
or renal insufficiency
Because delayed excretion of the drug, resulting in its
accumulation, may cause hypoglycemia
The sulfonylureas traverse the placenta and can deplete
insulin from the fetal pancreas;
Therefore, type II DM pregnant women should be
treated with insulin

12. Structures of Sulfonylureas

13. Structures of Sulfonylureas

14. Structure Activity Relationship of
Sulphonylurea
All are substituted arylsulfonylureas that differ by substitutions at
The para position on the benzene ring (R1) and
One nitrogen residue of the urea moiety (R2)
The benzene ring should contain one substituent, preferably at the
para position
The typical sulphonylurea is a mono substituted (usually para)
aromatic sulphonylurea
That has a bulky aliphatic substituent on the non-sulphonyl
attached nitrogen of urea
Small alkyl groups, such as methyl or ethyl
 Are not active or low activity

15. Structure Activity Relationship of Sulphonylurea cont.
In first generation analogues, the aromatic
substituent is a
Relatively simple atom or group of atoms
Such as methyl, amino, acetyl, chloro,
bromo, methylthio, or trifluoromethyl
groups
These substituents seems it enhance
hypoglycemic activity

16. Structure Activity Relationship of
Sulphonylurea cont.
 However, the second generation analogues have a
larger p-(β-arylcarboxyamidoethyl) group that
leads to
Significantly higher potency
It is believed that this is because of a specific
distance between the nitrogen atom of the
substituent and the sulfonamide nitrogen
atom

17. Structure Activity Relationship of Sulphonylurea
cont.
 The group attached to the terminal nitrogen should
be of certain size and should impart lipophilic
properties to the molecule
 The N-methyl are inactive
 N-ethyl have low activity
 While N-propyl to N- hexyl are most active
Activity is lost if N-substituent contains 12 or
more carbons

18. Meglitinides (Glinides)
 Like the sulfonylureas, the meglitinides act to lower blood
glucose levels by stimulating the release of insulin from the
pancreas
 This action is dependent on the ability of the beta cell in the
pancreas to produce some insulin
 However, the action of the meglitinides is more rapid than that of
the sulfonylureas and their duration of action is much shorter
 Because of this they must be taken three times a day
 Examples of the meglitinides include nateglinide (Starlix) and
repaglinide (Prandin)
 Like sulfonylureas, repaglinide stimulates insulin release by
closing ATP-dependent K+
channels in pancreatic β-cells

19. Structure Activity Relationship of Sulphonylurea &
Meglitinides
Hypoglycemic
sulfonylureas and glinides
contain an acidic
functional group (A in Fig.)
 That is required for
insulinotropic activity
 In all of the marketed
drugs of this class
 The acidic group is
attached to a phenyl ring
(B in Fig.)

20. Structure Activity Relationship of Sulphonylurea & Meglitinides cont.
The acidic group is
generally
Sulfonylurea
 Propionate, or
Carboxylate
Although compounds
containing other acidic
moieties like

Sulfonylsemicarbazide
s

Sulfonylaminopyrimidines
 Sulfonylcyanoguanidines
and
Sulfonamidonitroethylen

21. Structure Activity Relationship of Sulphonylurea &
Meglitinides cont.

Substitution on the acidic
function with a pendant lipophilic
group (C in Fig.)
Greatly enhances affinity for
the SUR-l and
Increases selectivity for SUR-l
over related
SUR-2A receptors found in
heart and skeletal muscle
and
SUR-2B receptors found in
smooth muscle
 In the earliest sulfonylureas, this
substituent is often
An N-propyl or N-butyl group
Whereas cycloalkyl groups are
most common in later compounds

22. Structure Activity Relationship of Sulphonylurea &
Meglitinides cont.
The pendant lipophilic
group cannot be attached to
benzoic acid derivatives like
repaglinide
But, it has been proposed
that the alkyl group of the
2-ethoxy substituent on the
phenyl ring (C) of this
compound
Occupies a similar site
on the receptor
Phenylalanine derivatives
like nateglinide have a
chiral center adjacent to the
carboxylate
In these compounds, the R
configuration at this center
is required for activity

23. Structure Activity Relationship of Sulphonylurea &
Meglitinides cont.
The acidic group in these
agents is attached to a
phenyl ring
Which is most often
substituted para to the
acidic function
In first generation
sulfonylureas
The para-substituents are
small groups like methyl,
acetyl, or chloro
Introduction of larger
groups composed of an
amido linker (D)
Attached to an aromatic
or heterocyclic tail (E)
Greatly increases the
potency of the second-
generation compounds

24. Structure Activity Relationship of Sulphonylurea & Meglitinides cont.
In the amido linker
The carbon and
nitrogen atoms of an
amide are incorporated
into a four-atom chain
With the amido
nitrogen occupying
the third position
from the phenyl ring
In the sulfonylureas
glyburide, glipizide, and
glimepiride
The carbon atom of
the amido carbonyl
group is at the fourth
position

25. Structure Activity Relationship of Sulphonylurea & Meglitinides cont.

Some benzoic acid derivatives
like meglitinide

Which has tolbutamide like
potency have a similar
arrangement of the amido
linker

The arrangement in which the
carbonyl is at the second position
as in repaglinide or the
sulfonylurea

Also affords highly potent
compounds

In this alternative, alkyl
substitution of the carbon at the
fourth position

Improves potency and activity
resides in the S- enantiomers
in both sulfonylurea and
benzoic acid derivatives

26. Structure Activity Relationship of Sulphonylurea &
Meglitinides cont.
Within the amido linker
The carbonyl group may
be more important than the
amide NH, and
It has been suggested that
each alternative chain
arrangement positions its
respective oxo function to
accept a hydrogen bond
from the same donor group
in the SUR-l protein
Nateglinide lacks an
equivalent to the
Amido linker (D in Fig.) &
Aromatic or heterocyclic
tail (E in Fig.)

27. Structure Activity Relationship of Sulphonylurea &
Meglitinides cont.

The amido linker found in second-
generation sulfonylureas and
repaglinide

Terminates in an attachment to
an aromatic or heterocyclic
group (E in Fig.)

Which is often substituted
ortho to the point of
attachment

Substituents such as alkyleneimino,
alkoxy, or oxo having an oxygen or
nitrogen atom adjacent to the ring

Afford potent compounds

Glipizide lacks this ortho
substituent

But the pyrazino nitrogen may
serve a similar function in binding

28. Insulin-Sensitizing Agents
 Two subclasses of insulin-sensitizing agents are
currently available:
The biguanides and
The thiazolidinediones
 They are described separately because drugs in these
subclasses
Do not share a common mechanism of action
and
Are not structurally similar

29. Biguanides
A biguanide refers to a structure where
Two guanidine molecules are linked through common
NH- link
Example: Phenformin, Metformin
Biguanides
Increase insulin sensitivity in liver and muscle
Inhibit glucose synthesis and release by the liver, and
Enhance the ability of tissues to take up glucose
It enhances insulin sensitivity and is not effective in the
absence of insulin
A biguanide differs from the sulfonylureas in
Not stimulating insulin secretion
Hence, generally does not cause hypoglycemia, even in large
doses

30. Biguanides
Metformin
 Currently the only biguanide, acts by reducing hepatic glucose
production, largely by inhibiting gluconeogenesis and increasing
insulin sensitivity in muscle and fat cells
 These actions are mediated at least partly by activation of
AMP-activated protein kinase (AMP kinase)
 May be used alone or in combination with the sulfonylureas
 A very important property is its ability to reduce hyperlipidemia
(LDL and VLDL cholesterol concentrations fall and HDL cholesterol
rises)
 The patient often loses weight
 Considered by some experts as the drug of choice in newly
diagnosed Type II diabetics
• Adverse effects are largely gastrointestinal, including diarrhea,
nausea, abdominal discomfort
• Lactic acidosis, a serious often fatal side effect associated with
biguanides, is rare in metformin

31. Biguanides
Metformin
The liver normally releases glucose by detecting the level of
circulating insulin
When insulin levels are high, glucose is available in the blood,
and the liver produces little or no glucose
When insulin levels are low, there is little circulating glucose, so
the liver produces more glucose
In type 2 diabetes the liver may not detect levels of glucose in the
blood and, instead of regulating glucose production, releases
glucose despite blood sugar levels
Metformin sensitizes the liver
To circulating insulin levels and reduces hepatic glucose
production
The only drug that has been demonstrated to reduce
macrovascular events in type 2 DM

32. Structure-Activity relationship of
Biguanide
 The available data on the relationship of structure to
hypoglycemic activity for substituted biguanides
result from a very limited number of studies,
generally in healthy animals
 Alkyl substitution at R1
Increases activity through n-pentyl
But decreases with
Longer chain length, branching, or with
cyclic alkyl substituents
 When R1 is aralkyl, phenethyl
 The compound become most potent
 Potency is highest with a
 Hydrogen or methyl substituent at R2

33. Thiazolidinediones
They are the most recently introduced class of oral
agents for treatment of type 2 diabetes
Improving insulin sensitivity and lowering blood
glucose, free fatty acid, and triglyceride levels
They are a group of structurally related peroxisome
proliferator-activated receptor γ (PPARγ) agonists
The PPARγ receptor is a member of the nuclear
hormone receptor family of ligand-activated
transcription factors that
Regulates gene expression of several genes
involved in fatty acid and carbohydrate
metabolism and adipocyte differentiation

34. Thiazolidinediones cont.
 They decrease insulin resistance and increase insulin
sensitivity by modifying several processes, with the end
result being
Decreasing hepatic glucogenesis (formation of glucose
from glycogen) &
Increasing insulin dependent muscle glucose uptake
 Principally act by increasing insulin sensitivity in
peripheral tissues
Thus, are effective only when insulin is present but
also may lower hepatic glucose production
 Increase glucose transport into muscle and adipose tissue
by enhancing the synthesis and translocation of specific
forms of the glucose transporters
 Also activate genes that regulate fatty acid metabolism in
peripheral tissue

35. Thiazolidinediones cont.
 Some peripheral actions may be secondary to the
stimulation of adiponectin release by adipocytes
 Adiponectin increases insulin sensitivity, reportedly
by elevating AMP kinase
Which stimulates glucose transport into muscle
and increases fatty acid oxidation
 Examples of the thiazolidinediones are rosiglitazone
(Avandia) and pioglitazone (Actos)

36. Thiazolidinediones cont.
 They were developed as oral antidiabetic agents in
1997 (commercially known as glitazones)
 The first thiazolidinedione, troglitazone, was taken
off the market in 1999 because of its hepatotoxicity
 Rosiglitazone and pioglitazone are now available for
clinical use
They are extremely potent in reducing insulin
resistance
They can be combined with insulin or other classes
of oral glucose lowering agents

37. SAR of Thiazolidinediones
Fig. Common structural features found in thiazolidinedione PPARγ
agonists & related compounds

38. SAR of Thiazolidinediones
Thiazolidinedione
hypoglycemic agents can be
viewed as being composed
of an acidic head group
connected to a lipophilic
tail by a phenoxyalkyl
linker
The pka value for
thiazolidinediones is about
6.8, and thus these
compounds are partially
ionized at physiological pH
This appears to be
important, given that
removal of the acidic
function by N-methylation
leads to loss of activity Fig. Common structural features found in
thiazolidinedione PPARγ agonists & related compounds

39. SAR of Thiazolidinediones
Other acidic
moieties,
heterocyclic groups
like oxazolidinediones
and particularly α-
substituted
carboxylic acids, can
also replace the
thiazolidinedione ring
The α-substituted
carboxylic acids are
often highly potent
but may not be
selective for PPARγ
Fig. Common structural features found in
thiazolidinedione PPARγ agonists & related compounds

40. SAR of Thiazolidinediones
There is a chiral center
at the 5 position of the
thiazolidinedione ring, but
this is not
configurationally stable
under physiological
conditions
For analogous α-
substituted carboxylic
acids, the PPARγ activity
resides in the S-
enantiomer
Fig. Common structural features found in
thiazolidinedione PPARγ agonists & related compounds

41. SAR of Thiazolidinediones
A phenoxyethyl group
(Fig., n = 2) as the central
phenoxyalkyl linker is
commonly found to yield
highly active compounds in
SAR studies of hypoglycemic
thiazolidinediones
Often shorter chain
lengths (Fig., n = 1) or
inclusion of the
phenoxyethyl group into a
heterocyclic ring also leads
to active compounds
Fig. Common structural features found in
thiazolidinedione PPARγ agonists & related compounds

42. SAR of Thiazolidinediones
In the lipophilic tail,
incorporation of a wide
variety of mostly aromatic
and heteroaromatic groups
has produced active agents
In a very limited study, the
hypoglycemic potency in a
series of oxazolidinediones
with variations in this
lipophilic tail was found to
increase with increasing log P
The thiazolidinedione ring
binds in a polar site, making
hydrogen bonds with groups
in the side chains of His-449,
Tyr-473, His-323, and Ser-289
Fig. Common structural features found in
thiazolidinedione PPARγ agonists & related compounds

43. α-Glucosidase Inhibitors
 Lower blood glucose by delaying the
Digestion of carbohydrates and
Absorption of carbohydrates in the intestine
 E.g., Acarbose( Precose) and Miglitol (Glyset)
 Reduce intestinal absorption of starch, dextrin, and
disaccharides by inhibiting the action of α-glucosidase in the
intestinal brush border
 Consequent to this delayed carbohydrate absorption, the
postprandial rise in plasma glucose is blunted in both normal and
diabetic subjects
 May be used
As monotherapy in elderly patients or
In patients with predominantly postprandial hyperglycemia
 Typically are used in combination with other oral antidiabetic
agents and/or insulin
 The drugs should be administered at the start of a meal

44. α-Glucosidase Inhibitors cont.
Acarbose
 Inhibits α-glucosidase in the intestinal brush border
 Thus, decreases the absorption of starch and disaccharides
Consequently the postprandial rise of blood glucose is blunted
 Unlike the other oral hypoglycemic agents, acarbose does
not
Stimulate insulin release from the pancreas nor does it
increase insulin action in peripheral tissues
Thus, does not cause hypoglycemia
 Can be used
As monotherapy in those patients being controlled by
diet or
In combination with other oral hypoglycemic agents,
or with insulin
 It is poorly absorbed and its major side effects are
flatulence, diarrhea, and abdominal cramping