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1. Oral hypoglycemic
Ravish Yadav

2. SYNTHETIC HYPOGLYCEMIC AGENTS
I. SULFONYLUREAS
• Sulfonylureas became widely available in 1955 for the treatment of mild
diabetes and are still the drugs of choice
• The sulfonylureas may be represented by the following general
structure:
1. These are urea derivatives with an arylsulfonyl group in the 1-position and an aliphatic
group at the 3-position.
2. The aliphatic group, R’, confers lipophilic properties to the molecule.
3. Maximal activity results when R’ consists of three to six carbon atoms, as in
chlorpropamide, tolbutamide, and acetohexamide.

3. 4. Aryl groups at R’ generally give toxic compounds. The R group on the aromatic ring
primarily influences the duration of action of the compound.

5. First generation sulphonyl urea
1. Tolbutamide
• Tolbutamide is absorbed rapidly in responsive diabetic patients
• Metabolism:
• It is oxidized rapidly in vivo to 1-
butyl-3-(p-carboxyphenyl)
sulfonylurea, which is inactive.
• The metabolite is freely soluble
at urinary pH, hence the urine is
strongly acidified.
Tolbutamide should be used only
when the diabetic patient
is an adult or shows adult-onset
diabetes

6. 2. Chlorpropamide
• This drug is more resistant to conversion to inactive metabolites than tolbutamide
and, as a result, has a much longer duration of action
• It has also been reported that almost 50% of the ‘drug’ gets usually excreted as
metabolites, with the principal one being hydroxylated at the C-2 position of the propyl-
side chain
• Use: The therapeutic application of this ‘drug’ is limited to such subjects having a
history of stable, mild to moderately severe diabetes mellitus who still retain residual
pancreatic β-cell function to a certain extent

7. 3. Tolazamide
• Tolazamide, is an analogue of tolbutamide and it is as effective as tolbutamide.
• Tolazamide is more potent than tolbutamide and is nearly equal in potency to
chlorpropamide.
• In studies with radioactive tolazamide, investigators found that 85% of an oral dose
appeared in the urine as metabolites that were more soluble than tolazamide itself.

8. 4. Acetohexamide
• It is related chemically and pharmacologically to tolbutamide and chlorpropamide.
Like the other sulfonylureas, acetohexamide lowers the blood sugar level, primarily by
stimulating the release of endogenous insulin.
• Acetohexamide is metabolized in the liver to a reduced form, the α-hydroxyethyl
derivative.
• This metabolite possesses hypoglycemic activity.
• Acetohexamide is intermediate between tolbutamide and chlorpropamide in potency
and duration of effect on blood sugar levels.

9. Second-Generation Sulfonylureas
1. Glipizide
• It is a cyclohexyl sulfonylurea analogue similar to acetohexamide and glyburide
• It is employed for the treatment of Type 2 diabetes mellitus which is found to be 100
folds more potent than tolbutamide in evoking the pancreatic secretion of insulin.
• It essentially differs from other oral hypoglycemic drugs wherein the ensuing tolerance to
this specific action evidently does not take place.
• The primary hypoglycemic action of this ‘drug’ is that it up regulates the insulin
receptors in the periphery. It does not exert a direct effect on glucagon secretion.
Metabolism: The ‘drug’ gets metabolized via oxidation of the cyclohexane ring to the
corresponding p-hydroxy and m-hydroxy metabolites
Use: (a) Treatment of non-insulin dependent diabetes mellitus (NIDDM) since it is effective
in most patients who particularly show resistance to all other hypoglycemic drugs
(b) Differs from other oral hypoglycemic drug because it is found to be more effective
during eating than during fasting.

10. 2. Glyburide
• It is mostly used for Type 2 diabetes melitus. It is found to be almost 200 times as
potent as tolbutamide in evoking the release of insulin from the pancreatic islets..
• SAR of Glyburide
• The presence of ‘R’ in
glyburide potentiates the
hypoglycemic activity 200
times, whereas the
heterocyclic nucleus in
glipizide potentiates 100
times in comparison to
tolbutamide
Pyrazine

11. 3. Glimepiride
• It is very similar to glipizide (Instead of the pyrazine ring found in glipizide, glimepiride
contains )
• It is metabolized primarily through oxidation of the alkyl side chain of the pyrrolidine,
with a minor metabolic route involving acetylation of the amine.
• Its hypoglycaemic activity is very much akin to glipizide.

12. 4. Gliclazide.
• It is very similar to tolbutamide, with the exception of the bicyclic heterocyclic ring found
in gliclazide.
• The pyrrolidine increases its lipophilicity over that of tolbutamide, which increases its
half-life.
• p-methyl is susceptible to the same oxidative metabolic fate as observed for tolbutamide,
namely, it will be metabolized to a carboxylic acid.

13. Cyclopentane ortho anhydride
as raw materials, ammoniates
to obtain cyclopentane
phthalimide. It reacts to obtain
azabicyclo through catalytic
reduction by catalysts like
LiAlH4, KBH4/ZnCl2 or black
platinum. And then azabicyclo
reacts to give N-3-azabicyclo [3,
3, O] octane hydrochloride by
nitrosation, zinc reduction.
Finally it reacts with toluene
sulfonylurea to obtain gliclazide
through condensation.

14. Nonsulfonylureas—Metaglinides
• Meglitinides (glinides) make up a class of drugs used to treat diabetes type 2.
• They bind to an ATP-dependent K+ (KATP) channel on the cell membrane of
pancreatic beta cells in a similar manner to sulfonylureas but have a weaker binding
affinity and faster dissociation from the SUR1 binding site.
• These agents tend to have a rapid onset and a short duration of action
 There are two major differences between these seemingly similar classes of agents.
The first is that the metaglinides cause much faster insulin production than the
sulfonylureas. Hence, the metaglinides should be taken during meals, as the
pancreas will produce insulin in a much shorter period.
 The second difference is that the effects of the metaglinides do not last as long as the
effects of the sulfonylureas (last less than 1 hour, whereas sulfonylureas continue to
stimulate insulin production for several hours) One advantage of a short duration of
action is that there is less risk of hypoglycaemia

15. 1. Repaglinide.
• With a fast onset and a short duration of action, the medication should be taken
with meals. It is oxidized by CYP 3A4, and the carboxylic acid may be conjugated to
inactive compounds
• Less than 0.2% is excreted unchanged by the kidney, which may be an advantage
for elderly patients who are renally impaired.
• The most common side effect involves hypoglycemia, resulting in shakiness,
headache, cold sweats, anxiety, and changes in mental state.
• This specific metabolism may be reasonably inhibited by certain drug substances’,
for instance miconazole, ketoconazole, and erythromycin.

16. 2. Nateglinide
it is a phenylalanine derivative and represents a novel drug in the management of type 2
diabetes.

17. II- THIAZOLINDIONES
 The thiazolindiones represent a novel nonsulfonylurea class of hypoglycemic agents for
the treatment of NIDDM.
 Like the sulfonylureas, these agents requires a functioning pancreas that can
successfully secrete insulin from cells.
 Although insulin may be released in normal levels from the cells, peripheral sensitivity
to this hormone may be reduced or lacking.
 MOA: The thiazolidinediones are highly selective agonists for the peroxisome
proliferator activated receptor- (PPAR), which is complexed with retinoid X
receptor(RXR) mainly in adipose tissue, but also in muscle and liver. This leads to
transcription of insulin-sensitive genes and a wide variety of actions:
1. Increase in glucose uptake (adipose, muscle and liver)
2. Increase in Lipogenesis (glucose+ fatty acids)
3. Increase in fatty acid upatake, glycolysis and glucose oxidation (muscle)
4. Decreases in gluconeogenesis and glycogenolysis ( liver)

19. 1. Rosiglitazone
 The molecule has a single chiral centre and is present as a racemate. Even so, the
enantiomers are functionally indistinguishable because of rapid interconversion.
2. Pioglitazone
 Although the molecule contains one chiral centre, the compound is used as the
racemic mixture.
 This is primarily a result of the in vivo interconversion of the two enantiomers.
 Thus, there are no differences in the pharmacological activity of the two enantiomers

20. 3. Troglitazone
 Troglitazone is highly bound (> 99%) to serum albumin. It gets metabolized solely in
the liver to several inactive compounds, including a sulphate-conjugate—a major
metabolite, and mostly excreted in the faeces.
 The ‘drug’ is not an insulin secretagogue
4. Ciglitazone

21. III- Bisguanides
Metformin.
• This class of agents is capable of reducing sugar absorption from the gastrointestinal
tract.
• Also, they can decrease gluconeogenesis while increasing glucose uptake by muscles
and fat cells.
• These effects, in turn, lead to lower blood glucose levels. Unlike the sulfonylureas,
these are not hypoglycemic agents but rather can act as antihyperglycemics
• They have the inability to stimulate the release of insulin from the pancreas.
• Often, metformin is coadministered with the nonsulfonylureas to improve the
efficacy of those agents.

22. IV- GLP-1 agonists
 GLP-1 is a potent antihyperglycemic hormone, inducing the β-cells of
the pancreas to release the hormone insulin in response to rising glucose, while
suppressing glucagon secretion.
 It does not cause hypo glycemia because GLP-1 no longer stimulates the β-cells to
release more insulin when blood glucose levels are in the fasting range.
 Additionally, GLP-1 appears to restore the glucose sensitivity of pancreatic β-cells.
The mechanism may involve increased expression of GLUT2 receptors on the surface
of the β-cells; GLUT-2 is a carrier protein on the cell surface that facilitates the
movement of plasma glucose across the cell membrane, allowing them to sense the
level of glucose in circulation and release insulin when levels begin to climb.
 GLP-1 may also sensitize β-cells by increasing the expression of glucokinase,
an enzyme in the β-cells that stimulates insulin production and release in response
to glucose entering the cell.
 GLP-1 is also known to inhibit the programmed cell death (apoptosis) of pancreatic
β-cells, and to stimulate β-cell proliferation and differentiation.
 In addition, GLP-1 inhibits gastric secretion and motility. This delays and protracts
carbohydrate absorption and contributes to a satiating effect.

25. 1. Exenatide
• It displays biological properties similar to human glucagon-like peptide-1 (GLP-1)
• Exenatide is a 39-amino-acid peptide, an insulin secretagogue, with glucoregulatory
effects.
• It has a therapeutic advantage in its resistance to degradation by DPP-IV (which breaks
down GLP-1 in mammals)
GLP-1
agonist

26. 2. Liraglutide
 It is GLP-1(1–37) modified at Lys26: the -amino group is acylated with an (N-hexadecanoyl)
 -γ-yl moiety.
 It is a long-acting glucagon-like peptide-1 receptor agonist, binding to the same receptors
as does the endogenous metabolic hormone GLP-1 that stimulates insulin secretion
 A once-weekly injection has been approved
3. Sitagliptin and Vildagliptin (same)
 Sitagliptin is an oral antihyperglycemic (antidiabetic drug) of the dipeptidyl peptidase-4
(DPP-4) inhibitor class.
 This enzyme-inhibiting drug is used either alone or in combination with other oral
antihyperglycemic agents (such as metformin or a thiazolidinedione) for treatment
of diabetes mellitus type 2.
 MOA: Sitagliptin works to competitively inhibit the enzyme dipeptidyl peptidase 4 (DPP-
4). This enzyme breaks down the incretins GLP-1and GIP, gastrointestinal
hormones released in response to a meal.
 By preventing GLP-1 and GIP inactivation, they are able to increase the secretion of insulin
and suppress the release of glucagon by the alpha cells of the pancreas. This drives blood
glucose levels towards normal. As the blood glucose level approaches normal, the amounts
of insulin released and glucagon suppressed diminishes, thus tending to prevent an
"overshoot" and subsequent low blood sugar (hypoglycaemia) which is seen with some
other oral hypoglycaemic agents.

27. Dipeptidyl peptidase-4 (DPP-4) inhibitor class.

28. 5. Saxagliptin
• It is an oral hypoglycemic (anti-diabetic drug) of the dipeptidyl peptidase-4 (DPP-4)
inhibitor class of drugs.
• U.S. FDA added a warning about increased risk of heart Although saxagliptin improves
glycemic control, other approaches are necessary to reduce cardiovascular risk in
patients with diabetes.
• Saxagliptin is used as monotherapy or in combination with other drugs for the
treatment of type 2 diabetes.
6. Linagliptin
• Linagliptin is a DPP-4 inhibitor for treatment of type II diabetes.
• They may cause severe joint pain.

29. Development of Sitagliptin
•

30.  The -amino acid–lead compound (1) was discovered by screening of a large library of
compounds.
 Compound 2 bound with very high affinity to the enzyme but was not endowed with
useful oral bioavailability.
 Changing the metabolically labile ethyl substituent in compound 3 to trifluoromethyl
gave a compound (4) with acceptable bioavailability, albeit binding with considerably
lower affinity than molecule 2.
 Relocating the fluorines on the phenyl ring improved the binding affinity but a
cardiovascular side effect appeared in preclinical studies of 5 in dogs.
 Adding one additional fluorine increased the affinity and eliminated the worrisome
preclinical side effect; molecule 6 was ultimately marketed as sitagliptin phosphate

32. V- α-Glucosidase Inhibitors
 The enzyme -glucosidase is present in the brush border of the small intestine and is
responsible for cleaving dietary carbohydrates and facilitating their absorption into
the body.
 Inhibition of this enzyme allows less dietary carbohydrate to be available for
absorption and, in turn, less available in the blood following a meal.
 The inhibitory properties of these agents are greatest for glycoamylase, followed by
sucrose, maltase, and dextranase, respectively.
 Because these do not enhance insulin secretion when used as monotherapy,
hypoglycemia is generally not a concern when using these agents.
1. Miglitol
Miglitol, a desoxynojirimycin derivative, is chemically known as 3,4,5-piperidinetriol.
• In chemical structure, this agent is very similar to a sugar, with the heterocyclic
nitrogen serving as an isosteric replacement of the sugar oxygen.
• This feature allows recognition by the α-glucosidase as a substrate. This results in
competitive inhibition of the enzyme and delays complex carbohydrate absorption
from the gastrointestinal tract.

33. 2. Voglibose is an alpha-glucosidase inhibitor used for lowering post-prandial blood glucose
levels in people with diabetes mellitus.
• Voglibose delays the absorption of glucose
• Alpha glucosidase inhibitors delay glucose absorption at the intestine level and thereby
prevent sudden surge of glucose after a meal.
• There are three drugs which belong to this class, acarbose, miglitol and voglibose, of
which voglibose is the newest.

34. V-Insulin Analouges
 An insulin analogue is an altered form of insulin, different from any occurring in
nature, but still available to the human body for performing the same action as human
insulin in terms of glycemic control.
 These modifications have been used to create two types of insulin analogs: those
that are more readily absorbed from the injection site and therefore act faster than
natural insulin injected subcutaneously, intended to supply the level of insulin needed
at mealtime (prandial insulin); and those that are released slowly over a period of
between 8 and 24 hours, intended to supply the basal level of insulin during the day
and particularly at night-time (basal insulin).
1. Lispro
 It is a rapid-acting human insulin analogue used to lower blood glucose.
 Insulin lispro is produced by recombinant DNA technology utilizing a non-
pathogenic laboratory strain of Escherichia coli.
 Insulin lispro differs from human insulin in that the amino acid proline at position B28
is replaced by lysine and the lysine in position B29 is replaced by proline.
 Chemically, it is Lys(B28), Pro(B29) human insulin analog and has the empirical formula
C257H383N65O77S6 and a molecular weight of 5808, both identical to that of human
insulin.

35.  Hypoglycemia, or low blood sugar, is the most common side effect of insulin
lispro. Symptoms of low blood sugar may include headache, nausea, hunger,
confusion, drowsiness, weakness, dizziness, blurred vision, fast heartbeat,
sweating, tremor, trouble concentrating, confusion, or seizure (convulsions).

36. 2. Glargine insulin
• Insulin glargine, is a long-acting basal insulin analogue, given once daily to help
control the blood sugar level of those with diabetes.
• It consists of microcrystals that slowly release insulin, giving a long duration of action
of 18 to 26 hours
• Sometimes, in type 2 diabetes and in combination with a short acting sulfonylurea
(drugs which stimulate the pancreas to make more insulin), it can offer moderate
control of serum glucose levels.
• In the absence of endogenous insulin—type 1 diabetes, depleted type 2 (in some
cases) or latent autoimmune diabetes of adults in late stage—insulin glargine needs
the support of fast acting insulin taken with food to reduce the effect of prandially
derived glucose.

37.  Insulin glargine has a substitution of glycine for asparagine at N21 (Asn21) and two
arginine's added to the carboxy terminal of B chain.
 The arginine amino acids shifts the isoelectric point from a pH of 5.4 to 6.7, making the
molecule more soluble at an acidic pH and less soluble at physiological pH.
 The isoelectric shift also allows for the subcutaneous injection of a clear solution.