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Diabetes Mellitus
 The word Diabetes is applied to condition of excessive hunger.
 The other symptoms of Diabetes Mellitus are;
• weigh loss
• Hyperglycemia
• altered metabolism of lipids, carbohydrates, and proteins
• an increased risk of complications from vascular disease.
Clinical Diabetes Mellitus
1. Type 1 Diabetes: - known as insulin-dependant Diabetes Mellitus (IDDM) is
caused by an absolute deficiency of insulin.
– This results from immune-system-mediated destruction of pancreatic β-cells.
– Without insulin, the body's primary source of energy and the brain's only source
of energy, glucose, is unable to enter the cells. This leads to cells being energy
starved as well as elevated plasma blood glucose levels.
– Administration of exogenous insulin currently is the only method to effectively
resolve this hormone deficiency.
Clinical Diabetes Mellitus
2- Type 2 Diabetes: - known as non-insulin-dependant Diabetes
Mellitus (NDDM).
– Type 2 diabetes is a more complex disease. If one parent has type 2
diabetes, the risk of developing it is 38%, whereas if both parents are
affected then, the risk of developing diabetes before age 60 is 60%.
– It is characterized by end-organ insulin resistance and/or a relative
deficiency in insulin secretion. Unlike the abrupt loss of β-cell function
characteristic of type 1 diabetes, the pancreatic β cells in type 2
diabetes undergo progressive deterioration over a fairly long time.
Cont.Clinical Diabetes Mellitus
2- Type 2 Diabetes: - known as non-insulin-dependant Diabetes Mellitus
(NDDM).
– At this point, blood glucose levels likely appear normal and the patient is
asymptomatic.
– For most patients with type 2 diabetes, resolution of their metabolic
disease may occur with appropriate lifestyle changes, including a well
balanced diet and regular exercise.
– For those type 2 patients who are unable to achieve normal blood
glucose levels, several classes of oral agents are available that target
various biochemical processes associated with insulin secretion and/or
insulin receptor sensitivity
Cont.Clinical Diabetes Mellitus
3-Gestational Diabetes

It is classified as any degree of glucose-intolerance that first occurs during
pregnancy, typically during the third trimester.

The risk factors associated with developing GDM include previous history of
GDM, obesity, glycosuria, or a family history that includes diabetes.
Synthetic Hypoglycemic Agents
Definitions
A key indicator of diabetes is persistent fasting blood
glucose levels above 11.1 mmol/L which arise from
defective conversion of glucose into energy.
-The plasma levels of FPG≥7.0mmol/L or PPG ≥11.1mmol/L
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Classification of Hypoglycemic Drug
 Sulfonylureas
 Biguanides
 α-Glucosidase inhibitors
 Thiazolindiones
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Sulfonylureas
1st generation
2nd generation
3rd generation
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








Tolbutamide
Chlorpropamide
Acetohexamide
Tolazamide
Gliclazide
Glibornuride
Glibenclamide
Glipizide
Gliquidone

 Glimepiride
1-First and second generation
sulfonylureas
First and second generation sulfonylureas
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Members of 1st generation sulfonylureas
Mechanism of action
•
They stimulate the release of insulin; they interact with receptors on
pancreatic β-cells to block ATP-sensitive potassium channels. This in turn
leads to opening of calcium channels which produce an influx of calcium
resulting in β-cells production of insulin.
•
These drugs are effective in patients with type 2 diabetes whose insulinsecreting capacity is intact but whose ability to produce adequate insulin in
the presence of elevated glucose has been lost.
•
They can cause hypoglycemia, because these drugs can stimulate insulin
secretion even when glucose levels are low.
Sulfonylureas
2-(p-aminobenzenesulfonamido)-5-isopropyl -thiadiazole (IPTD)
 At same time these effects were noted, the synthesis
of sulfonylurea such as Carbutamide, so far active as
hypoglycemic agents, was reported.
 Since then, about 12, 000 sulfonylureas have been
tested, and about 10 are currently on the market.
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Structure - Activity Relationships
 The benzene ring should contain one substituent, preferably in the para position.
The substituents that seem to enhance hypoglycemic activity are methyl, amino,
acetyl, chloro, bromo, methylthio, and trifluoromethyl groups.
 Compounds with p-(-b-arylcarboxamidoethyl) substituents (the second
generation agents) are orders of magnitude better than the first generation
agents. It is believed that this is because of a specific distance between the
nitrogen atom of the substituent and the sulfonamide nitrogen atom.
 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 Nsubstituent contains 12 or more carbons
Cont.Structure activity relationship
• There must be a reasonable bulk group on the urea nitrogen; methyl and
ethyl compound are not active.
• There is only one (normally para substituent) on the sulfonyl aromatic ring.
• Many substituents are active, and the p-(β-arylcarboxamidoethyl) grouping
seen in the second generation compounds is consistent with a high
potency.
• The spatial relationship between the amide nitrogen of the substituent and
the sulfonamide nitrogen is important.
Synthesis of Tolbutamide
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Acidic property
Tolbutamide shows acidic property，it can be
dissolved in base.
odour
Unstable under acidic condition.
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Members of 1st generation sulfonylureas
Metabolism
Metabolism of Tolbutamide
 Tolbutamide is absorbed rapidly in responsive diabetic patients. The
blood sugar level reaches a minimum after 5-8 h.
 It is oxidized rapidly in vivo to derivative with hydroxyl group (I) or
derivative with carboxyl group (II), which are inactive.
O O
O
S
HO
N
H
N
H
I
O O
O
S
HO
O
N
H
N
H
II
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Members of 1st generation sulfonylureas
Metabolism
• Chloropropamide undergoes slow hydroxylation on the propyl chain to
afford 2’ and 3’-hydroxy chloropropamide. Because these processes are
slow, chloropropamide is a long lasting drug.
Members of 2nd generation sulfonylureas
Glibenclamide
1-[[p-[2-(5-chloro-o-anisamido)ethyl]-phenyl]sulfonyl] -3-cyclohexylurea.
 Second-generation oral hypoglycemic agent.
 The drug has a half-life elimination of 10h, but its hypoglycemic
effect remains for up to 24h.
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Glibenclamide, Doanil, Glyburide
Synthesis
SO2Cl
SO2NH2
NH4OH
+ ClSO3H
HN (H2C)2
HN (H2C)2
HN (H2C)2
COCH3
COCH3
H+
Hydrolysis
Chlorosulpho
nic acid
COCH3
N-Acetylphenylamine
Cl
COCl
SO2NH2
SO2NH2
COCH3
HN (H2C)2
COCH 3
H2N (H2C)2
NCO
O
Cl
SO2NH
Cyclohexylisocyanate
HN
(CH2)2
COCH3
Cl
N
H
Hydrolysis of Glibenclamide
O O O
S
N
N
H
H
O
Cl
N
H
O O O
+
S
N
N
H
H2
O
H+
Cl
N
H


+
O O
OH
+
S
N C NH2
H
O-
O
Cl
N
H
H2 O

+
O O
OH2
S
N C
H
O
O
Cl
N
H
+

O O
S
NH2
O
Cl
N
H

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H2N
+
CO2 + H+
Members of 3rd generation
sulfonylureas
Metabolism of 2nd generation sulfonylureas
Glimepiride
1-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]
phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea.
 The third-generation oral hypoglycemic agent.
 Instead of the benzene ring found in Glibenclamide, Glimepiride contains a
pyrrolidine system.
 It is metabolized primarily through oxidation of the alkyl side chain of the
pyrrolidine, with a minor metabolic route involving acetylation of the amine.
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Metabolism of Glimepiride
Metabolism
Repaglinide
•
Repaglinide is a nonsulfonylurea that binds and block the
•
ATP-sensitive K+channels, resulting in insulin secretion from β-cells in addition to
having extrapanereatic effects
•
Repaglinide has a rapid onset and short duration of action compared to other
hypoglycemic drugs.
Repaglinide
• It is not associated with the prolonged hyperinsulinemia seen with
the sulfonylureas, and possibly for this reason, it produces fewer
side effects, including weight gain and potentially dangerous
hypoglycemia.
• Repaglinide is at least five fold more potent than glyburide on
intravenous administration and nearly 10-fold more active on oral
administration.
Metformin
 Metformin was discovered in 1957，it was not approved by the FDA
until 1994 for the treatment of type 2 diabetes.
 It is to lower blood glucose and to reduce cardiovascular complications.
.
 Over 6 million people were treated by it annually
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Metformin and phenoformin
Mechanism of Action
• Metformin and the other biguanides are described as insulin sensitizers; they act
in the liver by decreasing excessive, glucose production, most likely via reduced
gluconeogenesis resulting from an increased sensitivity to insulin.
• They also improve glucose utilization by restoring tissue sensitivity to insulin
• They appear to have their main action in the liver mitochondria via activation of
adenosine 5'-monophosphate-activated protein kinase (AMPK)
•Metformin can lower free fatty acid concentrations by 10 to 30%.
•The therapeutic effect of metformin requires the presence of insulin, and metformin
does not stimulate the release of insulin or other factors, such as glucagon.
•The drug does not induce hypoglycemia at any reasonable dose. For that reason,
metformine is usually said to be an antihyperglycemic rather than a hypoglycemic
agent.
1. Metformin HCl, Glucophage
HN
NH
C
H3C
H
N
HCl
C
N
NH2
CH3
1,1-Dimethylbiguanide HCl
Synthesis
CH3
NH
CH3
NH
HCl
+ CN
HN
H
N
H
N
NH2
Cyanoguanidine
NH
CH3 N
CH3
.HCl
NH2
4- Thiazolidinediones (Glitazones)
4- Thiazolidinediones (Glitazones)
Avandia
Function of Rosiglitazone Maleate
 Rosiglitazone maleate is not chemically or functionally related
to the sulfonylureas, the biguanides, or the alpha-glucosidase
inhibitors.
 It is an oral antidiabetic agent which acts primarily by
increasing insulin sensitivity.
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Side Effects
 -It is reported in May 2007 that the use of rosiglitazone was associated
with a significantly increased risk of heart attack, and an even higher risk
of death from all cardiovascular diseases.
 The FDA issued an alert on May 21, 2007.
 -In 2009 the study found that there was no increase in cardiovascular
hospitalization or death with rosiglitazone compared to metformin plus
sulfonylurea, but the rate of heart failure causing admission to hospital or
death was significantly increased.
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4- Thiazolidinediones (Glitazones)
•
-Like biguanides, thiazolidinediones are insulin sensitizers; however, they have a
different mechanism of action from that of the biguanides.
•
-The thiazolidinediones stimulate peroxisome proliferator-activated receptor
(PPAR)-γ stimulation, leading to the transcription of insulin-sensitive genes and,
subsequently, a wide variety of actions including increases in:
– glucose uptake (adipose, muscle, liver)
– lipogenesis (adipose, liver)
– fatly acid uptake and preadipocyte differentiation (adipose), and glycolysis and
glucose oxidation (muscle)
– In addition to decreases in gluconeogenesis, and glycogenolysis (liver).
•
The PPAR-γ expression is highest in adipose tissue.
4- Thiazolidinediones (Glitazones)
Metabolism
4- Thiazolidinediones (Glitazones)
Metabolism
4- Thiazolidinediones (Glitazones)
Metabolism
5- Dual PPARα and PPARγ Coactivators
•
Because of weight gain can occur as an undesirable effect, a drug that activated
both PPARα and PPARγ may be less prone to this side effect because of promotion
of fatty acid oxidation.
•
Activation of PPARα also is reported to reduce plasma triglyceride levels and to
increase high-density lipoprotein levels; these are very desirable actions for the
populations prone to type 2 diabetes.
5- Dual PPARα and PPARγ Coactivators
Muraglitazar and Tesaglitazar
•
Clinical trials demonstrated the expected benefits for muraglitazar, and it is
intended as a monotherapy or in combination with metformin.
•
Some concerns from the trials, however, is an increase, compared to placebo, in
serious cardiovascular events, including death, myocardial infarction and
congestive heart failure.
5- Dual PPARα and PPARγ Coactivators
Muraglitazar and Tesaglitazar
α-Glucosidase inhibitors
Miglitol
1-(2-Hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol
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Miglitol

White to pale-yellow powder is soluble in water, and
exhibits a pKa 5.9.
 In chemical structure, this agent is very similar to a
pyranose sugar , with a nitrogen atom replacing the
oxygen isosterically.
α-Glucosidase takes it in as a substrate and is thereby
competitively inhibited.
 The end result is a delay in the absorption of complex
carbohydrates from the gastrointestinal tract.
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6-α-glucosidase inhibitors
• To be absorbed from the gastrointestinal tract into the blood stream, the
complex carbohydrates we ingest as a part of our diet must first be
hydrolyzed to monosaccharides by α-glucosidase enzyme.
• The rationale for the α-glucosidase inhibitors is that by preventing the
hydrolysis of carbohydrate their absorption could be reduced.
• The oligosaccharidases responsible for final hydrolysis of these materials
are all located in the brush border of the small intestine and consist of two
classes:
1. The β-galaclosidases hydrolyze β-disaccharides, such as lactose,
2. α-glucosidases act on α-disaccharides, such as maltose, isomaltose,
and sucrose
6-α-glucosidase inhibitors
Structure activity relationship
•
Active α-glucosidase inhibitors have a common pharmacophore, comprising
a substituted cyclohexane ring and 4.6-dideoxy-4-amine-D-glucose unit
known as carvosine.
•
The secondary amino group of this structure prevents an essential carboxyl
group of the α-glucosidase from protonating the glycosidic oxygen bonds of
the substrate.
Acarbose (Precose)
• Acarbose competitvely inhibits glucoamylase and sucrase but has weak
effects on pancreatic α-amylase.
Voglibose
• It slows the release of monosacharides from polymeric materials,
and thereby lowers the glucose level.
Rimonabant
• Obesity is a major factor leading to type-2 diabetes. As such, effective
treatment of obesity may prevent or slow the onset of diabetes.
• Researchers hypothesized that if cannabinoids stimulate appetite in a
receptor-specific fashion, then blocking, central cannabinoid receptors
might lead to decreased appetite.
Cont.
Rimonabant
•Rimonabant was found to be a selective and potent antagonist of CB1
endocannabinoid receptor.
•Rimonabant was found to be a selective and potent antagonist of the receptor
and its administration led to the decreased consumption of fats and sugar,
resulting in weight loses.
Dulaglutide
is a glucagon-like peptide 1 receptor agonist (GLP-1
agonist) for the treatment of type 2 diabetes that can
be used once weekly.GLP-1 is a hormone that is
involved in the normalization of level of glucose in
blood (glycemia). The FDA approved dulaglutide for
use in the United States in September 2014]
Mechanism of action
Dulaglutide binding to glucagon-like peptide 1 receptor, slows gastric emptying
and increases insulin secretion by beta cells in the pancreas. Simultaneously the
compound reduces the elevated glucagon secretion by alpha cells of the
pancreas, which is known to be inappropriate in the diabetic patient. GLP-1 is
normally secreted by L cells of the gastrointestinal mucosa in response to a meal
Medical uses
The compound is indicated for adults with type 2 diabetes
mellitus as an adjunct to diet and exercise to improve glycemic
control. Dulaglutide is not indicated in the treatment of subjects
with type 1 diabetes mellitus or patients with diabetic
ketoacidosis. Dulaglutide can be used either stand-alone or in
combination with other medicines for type 2 diabetes, in
particular metformin, sulfonylureas, thiazolidinediones, and
insulin
Side effects
The most common side effects include gastrointestinal disorders, such as
dyspepsia, decreased appetite, nausea, vomiting, abdominal pain, diarrhea.[6]
Some patients may experience serious adverse reactions: acute pancreatitis
(symptoms include persistent severe abdominal pain, sometimes radiating to the
back and accompanied by vomiting), hypoglycemia, renal impairment (which
may sometimes require hemodialysis). The risk of hypoglycemia is increased if
the drug is used in combination with sulfonylureas or insulin