The document discusses diabetes mellitus (DM), its types, and treatments including insulin and oral hypoglycemic agents. Insulin is a protein produced by pancreatic beta cells with detailed descriptions of its chemistry, variations across species, and methods of synthesis, including recombinant DNA technology. Oral hypoglycemic agents, particularly sulfonylureas, biguanides, and thiazolidinediones, are reviewed for their mechanisms of action, efficacy, and suitability for different forms of diabetes.

1. Antidiabetic Agents
Insulin
Oralhypoglycemic agents
1

2. • DM- metabolic disorder characterized by
an increase in blood glucose
• Results from either inadequate insulin
secretion or insulin resistance or
both.
• Types of DM
– Type I (IDDM)
– Type II (NIDDM)
2

3. Chemistry of Insulin
• Insulin
– Secreted by beta cells of langerhan’s
– Polypeptide protein w/h contain 51 aas
a 21 aa A chain and a 30 aa B that are linked by
two disulfied bonds
– Has 3 disulphide linkages
• A7 & B7
• A20& B19
• A6 & A11
• In addition to the disulphide linkage the two chains are held together by
– Hydrophobic bonds
– Hydrogen bonds
– Salt linkage
• Synthesized from proinsulin w/h has negligible
hormonal activity
• Initially synthesized as a 110 aa preprohormone in the
pancreatic β cells which then undergoes translocation
through
the membrane of the rough endoplasmic reticulum 3

4. Chemistry of Insulin
Results the cleavage of 24 aas from N-terminous of the B
chain to produce pronisulin
• Inside endoplasmic reticulum the protein folds and the three
critical disulfide bonds formed
• Proinsulin undergo further modification by catlyzation with
calcium
dependent endopeptidases
4

5. 5

6. 6

7. 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
• Porcine Thr Ile Pro Lys Ala
• Bovine Ala Val Pro Lys Ala
7

8. Chemical modification of insulin
• Synthesis
• Semisynthesis
• Recombinant DNA
– Synthesis
– Total synthesis of human insulin was laborious and totally difficult
– Require more than 100 steps
– Synthetic insulin obtained in three steps
• Synthesis of chain A
• Synthesis of chain B
• Linking of the two by disulphide linkage
8

9. • Semi-synthesis
By coupling parts of native hormone with synthetic
peptide.
E.g. conversion of porcine insulin (B30=Ala) to
human insulin (B30=thr) by enzymatic removal of
sequence B23-30 and coupling with octapeptide of
human insulin
• Recombinant DNA
1st method- insertion of genes for production of
either chain A or chain B into a special strain of
E.coli & then combining the 2 chains chemically to
produce insulin w/h is structurally and chemically
similar to human insulin
9

10. • 2nd method- insertion of gene for the entire
proinsulin molecule into special E. coli
cells that are then grown by fermentation
process
– The connecting C- peptide is then enzymatically
cleaved from proinsulin
• Human insulin produced by rDNA
technology is less antigenic than that
produced from animal sources
 Lispro – is insulin obtained through r-DNA
10

11. SAR
1. Significant loss of hormonal activity is observed
up on removal of aa units from chain A
2. Activity is reduced by 10 - 20% by replacement of
A1 Gly with L-Ala but fully active if replaced by D-
Ala.
3. Several aa residues of B are not essential. The first 6
and the last 3 can be removed.
4. Breakage of disulphide linkage results in loss of
activity.
** Being protein insulin cannot be given orally as it is
digested by proteases and other enzymes.
11

12. • Insulin preparations
– Rapid acting
– Intermediate acting
– Long acting
• Zn- usually found in insulin
pharmaceutical formulations to promote
stability
• Dimerization of insulin occurs by complexing
with Zn ion
12

13. Insulin receptor
 The receptor for insulin is embedded in the plasma
membrane
composed of two alpha subunits and two beta
subunits linked by disulfide bonds
13

14. • Receptor binding region include: A-4 Glu, A-
5 Gln, A-19 Tyr, A-21 Asn, B-12 Val, B-16 Tyr,
B-24 Phe, and B-26 Tyr
14

15. Oral hypoglycemic agents
• Some milder forms of diabetes mellitus that do not
respond to diet management or weight loss and
exercise can be treated with oral hypoglycemic
agents.
• The success of oral hypoglycemic drug therapy is
usually based on a restoration of normal blood
glucose levels and the absence of glycosuria.
15

16. Drug classes
1. Sulfonylureas
2. Biguanides
3. Alpha glucosidase inhibitors
4.Thiazolidinediones
5.Meglitinides
16

17. Sulfonylureas
• Sulfonylureas are the most widely prescribed drugs
in the treatment of type II diabetes mellitus.
• The initial sulfonylureas were introduced nearly 50
years ago and were derivatives of the antibacterial
sulfonamides.
• Although their structural similarities to the
sulfonamide antibacterial agents are readily apparent,
the sulfonylureas possess no antibacterial activity.
17

18. • Increase the number of insulin receptors and
increase peripheral use of glucose.
• Effective only if have functioning beta cells.
• Primary side effect is hypoglycemia
18

19. Mechanism of
Action
• The primary mechanism of
action sulfonylureasis direct
stimulation of
of the
insulin
release from the pancreatic β-cells.
• At higher doses, these drugs
also hepatic glucose production
decrease
• sulfonylureas may possess additional
extra- pancreatic effects that increase insulin
sensitivity 19

20. • The sulfonylureas are ineffective for the management
of type I and severe type II diabetes mellitus,
– since the number of viable β-cells in these forms of
diabetes is small.
• Severely obese diabetics often respond poorly to the
sulfonylureas, possibly because of the insulin
resistance that often accompanies obesity.
20

21. • Sub classified as
– 1st generation
– 2nd generation
– 3rd generation
21

22. a. 1st 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
• They also tend to have more adverse drug interactions
than the second-generation sulfonylureas
22

23. R SO2NHCONHR'
Tolbutamide
Chlorpropamide
Tolazamide
Acetohexamide
Gliclazide
R
CH3
Cl
R'
n-Butyl
n- Propyl
CH3 N
CH3CO
CH3
N
23

24. In general these are eliminated in the urine as some parent compound
plus metabolites
Tolbutamide is one of the least potent oral hypoglycemics with short
duration due to rapid hydroxylation of para methyl substituent followed
by oxidation to the acid
In Chlorpropamide the para chloro protects from oxidation and thus has
a longer duration than tolbutamide. Also increases lipid solubility to
increase potency.
Tolazamide has a cyclic substituent that makes it approximately equal to
chlorpropamide in potency even though the para substituent is the
same as tolbutamide. Oxidized quickly as with tolbutamide, but the
alcohol formed has reasonable activity (active metabolite) so its overall
duration is longer than tolbutamide and shorter than chlorpropamide
Acetohexamide possesses ketone group that is rapidly reduced to the
alcohol but this is more active than the parent compound and has a
longer half-life. The 4 position on the hexane ring is also hydroxylated.
Duration is similar to tolazamide.
24

25. b. 2nd generation
• The second-generation sulfonylureas display
– A higher specificity and affinity for
the sulfonylurea receptor
– More predictable pharmacokinetics in terms of
time of onset and duration of action
– Fewer side effects.
25

26. R SO2NHCONH
R =
Cl
OCH3
CONHCH2CH2 Glibenclamide
R =
N
N
H3C
CONHCH2CH2 Glipizide
R =
H3CO
H3C
CH3
N CH2CH2
O
O Gliquidone
Due to their larger molecular size, biliary excretion becomes important
26

27. 3rd generation
Glimepiride
N
H3C
H3C
H
N H
N
S
O O
H
N
O
O
O CH3
27

28. SAR For sulfonylurea
• These are urea derivatives with an aryl sulfonyl group in the
1 position and an aliphatic group in the 3 position
• Small alkyl groups such as N-methyl is inactive , N-ethyl have
low active, N-propyl up to N-hexyl are most active while activity is
lost if substituent contains 12 or more carbons
• In first generation analogues, the aromatic substituents are
a relatively simple
atom or group of atoms
• Second generation analogues have a larger aromatic substituent
that leads to higher potency
• Sulfonylureas are weak acids with pKa values of approximately
5.0 with proton disociation from the sulfonyl attached nitrogen of
urea
• The R’ confers lipophilic property to the molecule 28

29. 2) Bigaunides
N
R
R'
H
N
NH2
NH NH
R R'
Phenformin
Metformin
Buformin
H
CH3
H
PhCH2CH2
CH3
n-Butyl
Their structures contain two guanidine molecules linked through common —NH— link
30
29

30. • MOA
– decrease gluconeogenesis while increasing glucose
uptake by muscle and fat cells by improving glucose
action
• Unlike the sulfonylureas, these are not hypoglycemic
agents but rather act as antihyperglycemics
• Metformin is approved for the treatment of patients with
NIDDM that are refractory to dietary management alone
30

31. 3) αlpha-Glucosidase Inhibitors
• Glucosidases are responsible for the catalytic cleavage of a
glycosidic bond in the digestive process of carbohydrates
with specificity depending on
 Number of monosaccharides
 The position of cleavage site
 The configuration of the hydroxyl groups in the substrate
• The α -glucosidase inhibitors primarily act to decrease
postprandial hyperglycemia by slowing the rate at which
carbohydrates are absorbed from the gastrointestinal tract.
• Work by preventing digestion of carbohydrates
• Alpha glucosidase inhibitors are saccharides w/h act
as competitive inhibitors of enzymes needed to digest
carbohydrates
• Oligosaccharides →glucose by alpha glucosidase(maltase,
amylase, sucrase)
• Inhibition of this enzyme reduces the rate of digestion
of carbohydrates
31

32. i. Acarbose
– is a complex oligosaccharide
– it delays CHO metabolism by inhibiting -
D- Glucosidase reversibly
– Freely availlabe for clinical use
32

33. MOA:
of
gastric
• Blocks the digestion of starch, sucrose and maltose.
• Acarbose decreases meal stimulated secretion
inhibitory polypeptide and other
gastrointenstinal
peptide
(inhibitors) hormones.
• There is smaller increase in post prandial blood sugar
level that leads to smaller increase in insulin level.
• Acarbose does not cause weight gain with the
therapeutic doses
33

34. HOH2C
O
H H
N
OH
HO
OH
Voglibose
OH
OH
ii. voglibose
is orally active inhibitor of -D-Glucosidase also used for
other CHO dependant disorders much more potent and
with fewer side effects than Acarbose
34

35. 4) Thiazolidinediones
• 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.
• Stimulate receptors on muscle, fat, and liver cells
• Results in increased uptake of glucose in periphery and
decreased production by the liver
• Thiazolidinediones
proliferator–
activated
activate the nuclear
peroxisome receptor (PPAR)γ
and modulate the
expression of insulin-sensitive genes
35

36. • Have a role in preserving β cell function in
diabetic patients by lowering peripheral
insulin demands- have insulin sparing effect
• Do not cause hypoglycemia-makes
them representative for antidiabetic
therapy
-their glucose lowering activity is
self limiting
36

37. • The patient who would benefit the most from a
thiazolidinedione is
– a type II diabetic with a substantial amount of insulin
resistance
37

38. 38

39. Meglitinides
• Nateglinide and repaglinide are representative of this group
of oral hypoglycemic agents
•
Rapeglinide Nateglinide
39