Chapter 1

Antidiabetic Drugs
 Overview of DM
• DM is not a single disease entity but rather a group of
metabolic disorders sharing the common underlying
feature of hyperglycemia

• Hyperglycemia in DM results from

– Defects in insulin secretion, insulin action, or, most
commonly, both
• It affects more than 120 million people world-wide
– It is estimated that it will affect 220 million by the
yr 2020

2
 Overview of DM …
• Type 1 DM
– An autoimmune disease in which islet destruction is
caused primarily by
• T lymphocytes reacting against as yet poorly
defined β-cell antigens, resulting in a reduction in
β-cell mass
– Genetic susceptibility & environmental influences
play important roles in the pathogenesis
– Most commonly develops in childhood, becomes
manifest at puberty & progressive with age

3
 Overview of DM …
• Type 2 DM
– Like Type 1 DM, the pathogenesis of type 2 DM
remains enigmatic
– Environmental influences, such as a sedentary life
style & dietary habits have a role
– Genetic factors are more important than in type 1 DM
– The 2 metabolic defects that characterize type 2 DM
• Insulin resistance
– ↓ed ability of peripheral tissues to respond to
insulin

4
 Overview of DM…
• Type 2 DM…
– β-cell dysfunction
• Manifested as inadequate insulin secretion in the
face of insulin resistance & hyperglycemia
NB: In most cases, insulin resistance is the 10 event &
followed by ↑ing degrees of β-cell dysfunction
• Type 3 DM
– The type 3 designation refers to multiple other specific
causes of an elevated blood glucose:
• Pancreatectomy , pancreatitis, non-pancreatic
diseases, drug therapy, etc

5
 Overview of DM…
• Type 4 DM
– Gestational diabetes (GDM) is defined as any abnormality in
glucose levels noted for the 1st time during pregnancy
– During pregnancy, the placenta & placental hormones create
an insulin resistance that is most pronounced in the last
trimester
– Risk assessment for DM is suggested starting at the 1st
prenatal visit
– High-risk women should be screened immediately
– Screening may be deferred in lower-risk women until the
24th to 28th wk of gestation

6
 Types of Antidiabetic Agents

A. Injectable antidiabetic agents: Insulins

B. Oral antidiabetic agents

Both aim to produce normal blood glucose states

7
I. Insulin
• Biosynthesis of Insulin
– The active insulin hormone is composed of a 21-aa A chain
& a 30-aa B chain that are linked by 2 disulfide bonds
– Separately, each chain is biologically inactive

– Insulin is initially synthesized as a 110-aa preprohormone

in the pancreatic β cells
• The preprohormone then undergoes translocation through the
membrane of the rough ER
• During this process, the cleavage of 24-aas from the N-terminus of
the B chain occurs to produce proinsulin
– Inside the rough ER, the protein folds, & the 3 critical
disulfide bonds form
8
 Insulin…
• Biosynthesis of Insulin…
– In the Golgi cpx, proinsulin undergoes additional
modification that is catalyzed by Ca2+ dependent
endopeptidases
• In this process, 4 basic aas as well as the connecting
C-peptide are removed via proteolysis
– →active form of the hormone found in the plasma
– In solution, insulin can exist as a monomer, dimer, or
hexamer
– In the pancreas, insulin is stored in its hexameric form
• In this form, 2 Zn ions are coordinated per insulin hexamer
– The t1/2 of insulin is 5-6 min, whereas the t1/2 of proinsulin
is approx 17 min
9
Primary structure of proinsulin, depicting cleavage sites to produce insulin.
 Insulin…
• Secretion of Insulin
– Secretion of insulin from the pancreas is very tightly
regulated
– When glucose enters the β cell (GLUT-2–facilitated
transport), it is phosphorylated by glucokinase to G6P
– The G6P is used to generate ATP, thereby changing the ratio
of ATP to ADP & prevents an K+ATP channel from functioning
→ depolarization of the β cells →activation of a voltage-
gated Ca2+ channel & Ca2+ flows into the β cells
– The elevated intracellular Ca2+ conc causes activation of
phospholipases A2 & C, & levels of IP3 rise →facilitates
additional release of Ca2+ into the cytosol
• The intracellular conc of Ca2+ are now sufficiently high to promote
insulin secretion from the β cells
11
Fig. One model of control of insulin release from the pancreatic beta cell by glucose &
by sulfonylurea drugs
 Insulin…
• Several classes of pharmacological agents alter the
regulation of insulin release

• α2-Adrenergic receptor agonist → Inhibits insulin

secretion
• α2-Adrenergic receptor antagonist → Promotes
insulin secretion
• β2-Adrenergic receptors agonists → Promotes insulin
secretion
• β2-Adrenergic receptors antagonists → Inhibits insulin
secretion
 Structure Activity Relationships (SAR)

• The active insulin is composed of a 21-amino acid A chain & 30-aa B

chain that are linked by two disulfide bonds.

Separately, each chain is biologically inactive.

structure of insulin
Structure Activity Relationships (SAR)..

• Significant loss of hormonal activity is observe up on

removal of aa units from chain A

Several aa residues of B are not essential

• Up to the first 6 & the last 3 can be removed
• Breakage of disulphide linkage results in loss of
activity

• Being protein insulin cannot be given orally as it is

digested by proteases & other enzymes
 Species variation
• Same structural framework but variable aa substitution

• Porcine insulin is the closest to human insulin

 Differences of insulin from different spps

Species A8 A10 B28 B29 B30
Human Thr Ile Pro Lys Thr
Lispro Thr Ile Lys Pro Thr
Porcine Thr Ile Pro Lys Ala
Bovine Ala Val Pro Lys Ala
 Solution Structure of Insulin
• The tertiary structure conformation buries a number of
hydrophobic A-chain residues in the interior of the peptide,
which improves water solubility & stability

• Only the insulin monomer is able to interact with insulin

receptors, & native insulin exists as a monomer at low,
physiological conc (<0.1 NM)

• Insulin dimerizes at the higher conc (0.6 mM) found in

pharmaceutical preparations, & at neutral pH in the
presence of zinc ions, hexamers form
– These zinc-associated hexamers also are the storage form of insulin
in β cells
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 Stability of Insulin
• Presently, all pharmaceutical preparations are either
solutions of Zn insulin or suspensions of insoluble forms
of Zn insulin
• A longer acting & more stable form of insulin is
protamine Zn insulin, which is prepared by ppt insulin in
the presence of Zn ions & protamine (a basic protein)
– Contain 2 Zn ions per insulin hexamer
• Shorter-acting & more useful preparation is neutral
protamine Hagedorn (NPH) insulin, which includes m-
cresol as a preservative → isophane insulin
– Six m-cresol molecules occupy cavities in the hexamer involving
the B1-B8 helix formed as a result of the presence of the m-
cresol

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 Stability of Insulin…
• Later , it was reported that when small additional
amounts of Zn ions were added to hexameric 2-Zn
insulin in neutral acetate buffer, insulin could be made to
crystallize in several forms with varying rates of
dissolution in water

– Thus, the rapidly soluble amorphous semilente insulin

is a 2-Zn insulin, &

– The crystalline, more slowly soluble ultralente insulin

is a 4-Zn form
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 Insulin Analogues
• Variations or removal of aa residues from the C-
terminus of the insulin B chain did not drastically change
the biological activity
– But could influence the rate of dimer formation or separation
• If dimer formation can be inhibited, rapid-acting insulins
may be obtained

• Thus, the various insulin analogues that have been

developed have substitutions in or additions to the C-
terminus starting at residue B28
– The resulting analogues have either a faster onset or
a longer duration of action relative to native insulin

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 Insulin lispro: Pro at position B28 has
been moved to B29, & Lys at position
B29 has been moved to B28
Insulin aspart: substitution of the B28
Pro with a negatively charged Asp

Insulin glulisine: substituting a Lys for

Asn at B3 & Glu for Lys at B29

Insulin glargine: attachment of 2

Arg molecules to the B-chain
carboxyl terminal & substitution
of a Gly for Asn at the A21
position →soluble in an acidic
Fig. Structure of human proinsulin (C-peptide plus A & B solution but ppt in the more
chains) and insulin neutral body pH after SC inj

Insulin detemir: terminal thr is dropped from the B30 position & myristic acid (a C-14 FA
chain) is attached to the terminal B29 Lys →prolong the availability of the injected
analog by ↑ing both self-aggregation in SC tissue & reversible albumin binding
 Faster-Acting Analogues
• Insulin lispro and insulin aspart:
– B28 Pro is replaced with a linear amino acid
– This change also results in a conformational change at the
C- terminus and, therefore, the ability of the insulin to
dimerize
– Both of these analogues dissociate into monomers faster,
& this produces a faster onset of action
– Both can be injected immediately before meals providing
for more convenient timing & more accurate calculation of
appropriate dosing
– These analogues also can be used in combination with
regular or NPH insulin

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 Longer-Acting Analogues
• Insulin glargine:
– This analogue results from the replacement of A21 Asn by
Gly & the addition of two Arg aas to the C- terminus of the
B chain
– The resulting analogue has an isoelectric point close to
seven, which results in precipitation on subcutaneous inj
– The analogue is slowly released from the resulting depot
– It produces minimal peak effects & has a duration of action
of 22-24 hrs
– It has been demonstrated to be comparable or slightly
better than NPH insulin at maintaining or reducing HbA1c
levels without nocturnal hypoglycemia

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 Longer-Acting Analogues..
• Insulin detemir:

– This analogue results from N-acylation of the B29 Lys with

14-carbon myristic acid

– The fatty acid side chain binds to plasma albumin to

produce a depot and longer action

– It is not as long-lasting as insulin glargine, & is injected BID

by DM pts

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II. Chemistry of oral antidiabetic agents
 Oral antidiabetic drugs used for the treatment of
Type II DM can be classified based on their chemical
structures as

1. Sulfonylureas (secretogogues)

2. Biguanides (sensitizers)

3. Alpha glucosidase inhibitors (enzyme inhibitors)

4. Thiazolidinediones (sensitizers)

5. Meglitinides (secretogogues)
  Sulfonylurea's are the most widely prescribed
drugs in the treatment of type II diabetes mellitus.
 The sulfonylurea agents are basically sulphonamide
structural analogues but they do not essentially possess
any ‘antibacterial activity’ whatsoever

O O
H H Sulphonamide
R1 S N C N R2
2 3
1
O

General chemical structure

.
 1. Sulfonylureas
• Sulfonylureas Contain a sulfonyl & a urea group
• The sulfonylurea portion is very water soluble
– It has an acidic amine & oxygen atoms for good
hydrogen bonding
• R 1 & R 2 are very lipophilic & account for differences in
overall potency, metabolism, duration & routes of
elimination
• Overall the drugs tend to be lipophilic & ionized at body pH
• 2nd generation are much more lipophilic than the 1st &
hence more potent
• Sulfonylureas are similar in chemistry to the sulfonamides
– Thus, potentially share toxicities and allergies

29
 SAR of sulfonylureas
• The typical sulfonylurea is a mono substituted (usually
para) aromatic sulfonylurea that has a bulky aliphatic
substituent on the nonsulfonyl-attached nitrogen of the
urea
– Small alkyl groups, such as methyl or ethyl, are not active
• 1st-generation analogues: the aromatic substituent is a
relatively simple atom or group of atoms (e.g., methyl,
amino, acetyl, chloro, bromo, methylthio, or
trifluoromethyl)
• 2nd-generation analogues: have a larger p-(β-
arylcarboxyamidoethyl) group that leads to significantly
higher potency

30
 SAR of sulfonylureas …
• Glimepiride: 2nd generation sulfonylurea
– It has a similar extended binding group like glyburide
& glipizide; however, differences in its
pharmacological profile may justify a separate
classification
• Sulfonylureas are weak acids, with pKa values of approx
5.0 with proton dissociation from the sulfonyl-attached
nitrogen of the urea
• Serum protein binding is high, so care must be taken
when administering with other highly protein bound
drugs

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 MOA of Sulfonylureas
• The principal action of the sulfonylureas is to stimulate
the release of insulin from β cells
• They act by affecting the K+ATP channel
– This channel is a hetero-octameric complex of two
subunits: a sulfonylurea receptor (SUR1) , & an
inwardly rectifying K+ channel (Kir6.2)
– On binding to SUR1, K+ efflux is blocked,
→depolarization of the membrane
– This depolarization opens voltage-dependent Ca2+
channels, → an influx of Ca2+
– At higher intracellular Ca2+ conc, Ca2+ -sensitive
proteins act to promote the release of stored insulin
from the cells
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 Sulfonylureas….
• These drugs are effective in pts with type 2 DM whose
insulin-secreting capacity is intact but whose ability to
produce adequate insulin in the presence of elevated
glucose has been lost
• All sulfonylureas exhibit both insulin-secreting &
extrapancreatic activities

• Glimepiride relies on extrapancreatic effects for a greater

proportion of its hypoglycemic effect

– It is possibly b/c of this that it is considered less likely to

produce unwanted hypoglycemia

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• These agents tend to cause weight gain,
hyperinsulinemia and hypopglycemia

 Sulfonylurea's are now divided into three sub-

groups, namely:
 1st generation and
 2nd generation
 3rd generation
 The first-generation sulfonylureas are not
frequently used in the modern management of
diabetes mellitus because of their

 relatively low specificity of action

 delay in time of onset

 occasional long duration of action, and

 a variety of side effects

 have more adverse drug interactions than the

second-generation sulfonylureas
 The second-generation sulfonylureas display
 A higher specificity & affinity for the sulfonylurea
receptor

 More predictable pharmacokinetics in terms of time of

onset and duration of action

 Fewer side effects.

 higher potency

 The second-generation sulfonylureas display higher

potency cause of large groups at p- position
 R SO2NHCONH

Cl

R= CONHCH2CH2 Glibenclamide

OCH3

N
CONHCH2CH2
Glipizide
R=
H3 C
N

H3 C
CH3
O Gliquidone
R=
N CH2CH2
H3CO

Glyburide (glibenclamide) the most potent

 Glimepiride typically is classified as a second
generation sulfonylureas and it has a similar
extended binding group like glipizide;
however, difference in its pharmacological
profile may justify a separate classification

Glimepiride

H3C
H
N H
N H
N
N
O S
H3C
O O O CH3
O
 no longer produced

H
R NH2
N
N
R'
NH NH

R R'

Phenformin H PhCH2CH2

Metformin CH3 CH3

Buformin H n-Butyl
 This class of drugs distinctly lower hepatic glucose
production, reduces intestinal absorption of glucose,
and ultimately improves insulin sensitivity
 They also decrease gluconeogenesis while increasing
glucose uptake by muscle and fat cells

 Unlike the sulfonylureas, these are not hypoglycemic

agents but rather act as Euglycemic agents

 Metformin is approved for the treatment of patients

with type 2 DM that are refractory to dietary management
alone
 Work by preventing the digestion of carbohydrates
 Startch, table sugar
 They act by competitively inhibiting α-
glucosidases, a group of enzymes in the intestinal
brush border epithelial cells that includes
glycoamylase, sucrase, maltase, and dextranase.
 Reduces rate of digestion of carbohydrates!

 The prolongation of the intestinal absorption of

carbohydrates results keeping postprandial
hyperglycemia under control.

 Alone does not cause hypoglycemia

i. Acarbose (Glucobay, Precose, Prandase)

 is a complex oligosaccharide

 it delays CHO metabolism by inhibiting -D-Glucosidase

 Does not cause hypoglycemia when used as monotherapy

ii.Voglibose
 Voglibose is newes, less side effects and Economical

 is orally active inhibitor of -D-Glucosidase

 much more potent and with fewer side effects than Acarbose

iii. Miglitol (Glyset)

 It also lowers blood-glucose level

 Cause hypoglycemia when used as monotherapy

 Acarbose

OH

OH OH
HOH2C H HO N
N
OH

HO OH
HO OH
OH
OH
Voglibose Miglitol
 Thiazolidinediones (sometimes termed glitazones)
are a novel class of drugs that were initially
identified for their insulin-sensitizing properties.

 They all act to decrease insulin resistance and

enhance insulin action in target tissues.

 Thiazolidinediones activate the nuclear peroxisome

proliferator–activated receptor (PPAR) ,γ and
modulate the expression of insulin-sensitive genes
 The patient who would benefit the most

from a thiazolidinedione is

 a type II diabetic with a substantial amount of

insulin resistance

 They do not cause hypoglycemia (similar to

metformin and acarbose ) when used as

monotherapy
 Repaglinide (Prandin) and Nateglinide (Starlix) are
novel oral blood glucose-lowering agents that are
distinct from all other antidiabetic agents in their
chemical structure, mechanism of binding to target
channels in beta-cells, and mode of elimination.
 Combination therapy with repaglinide/ Nateglinide
and metformin resulted in synergistic improvement
in glycemic control than monotherapy