SulfonylUreases and Biguanides B.Pharmacy 3rd Year Medicinal Chemistry II

1. ANTIDIABETIC
DRUGS
Medicinal Chemistry II
Anushka Kulkarni

2.  Anti-diabetic medications treat diabetes mellitus by lowering glucose levels
in the blood.
 With the exceptions of insulin, exenatide, and pramlintide, all are
administered orally and are thus also called oral hypoglycaemic agents or
oral antihyperglycemic agents.
 Diabetes mellitus type I is a disease caused by the lack of insulin.
 Insulin must be used in Type I, which must be injected.
 Diabetes mellitus type 2 is a disease of insulin resistance by cells.
 Treatments include: agents that increase the amount of insulin secreted by
the pancreas, agents that increase the sensitivity of target organs to insulin,
agents that decrease the rate at which glucose is absorbed from the
gastrointestinal tract.

3. Classification :
 Enhance Insulin secretion –
1.Sulfonylureas - First generation: Tolbutamide Second generation: Chlorpropamide,
Glipizide, Glimepiride.
2.Meglitinide analogues - Repaglinide, Nateglinide.
3. Glucagon-like peptide-1 (GLP-1) receptor agonists (Injectable drugs) - Exenatide,
Liraglutide.
4. Dipeptidyl peptidase-4 (DPP-4) inhibitors - Sitagliptin, Vildagliptin.
 Overcome Insulin resistance
1. Biguanides – Metformin.
2. Thiazolidinediones (PPAR activator) – Pioglitazone.
 Miscellaneous antidiabetic drugs –
1. α-Glucosidase inhibitors - Acarbose, Miglitol, Voglibose.
2. Sodium-glucose cotransport-2 (SGLT-2) Inhibitor – Dapagliflozin.

4. 1.SULFONYLUREA
S

5. Mechanism of Action -  Sulfonylureas stimulate the release of
insulin from βcells of the pancreas.
 These cells metabolize glucose in the
mitochondria to produce ATP, which
increases the intracellular ratio
ADP/ATP.
 The ATP sensitive K+channel is an
octameric heterocomplex consisting of
two units of the binding site for both
sulfonylurease and ATP, designated as
the sulfonylurea receptor type I (SUR1).
 Sulfonylurea binds to SUR1 which
increases the intracellular ratio
ADP/ATP which results in the closure of
ATP sensitive K channels, leading to
rapid influx of Ca+.
 Increased intracellular Ca2+ causes an
alteration in the cytoskeleton and
stimulates translocation of insulin
containing granules to the plasma
membrane and the exocytotic release of
insulin.

6. STRUCTURE ACTIVITY RELATIONSHIP
The pharmacophore is divided into four parts – 1. Para amino group, 2. Aromatic ring, 3.
Sulphonamide group and 4. N1 substitution.
1. Para amino group – The substituent on the benzene ring in Para position should be
substituted.
Substituents like methyl, acetyl, chloro, bromo, trifluromethyl and dithiomethyl enhance
antihyperglycemic activity.
Substitution should always be on Para position or else activity is lost.
The substituent must be lipophilic.

7. 2. Aromatic ring - It is the minimal structural requirement for antibacterial action.
It should always be Para substituted.
Other substituents result in formation of inactive compound.
3. Sulphonamide group -- It is essential for antibacterial activity.
The sulphur atom should be directly linked to the aromatic ring.
Substitution of free sulphonic group(-SO3H) instead of sulphonamide destroys activity.
Replacement by sulphinic acid (-SO2H) and acetylation at N4 retains activity.
Active form is in ionized form and maximum action is obtained at pH 6.6 – 7.4.
4. N1 substitution – N should be primary or secondary.
R2 should be substituted with H, aromatic ring or heterocyclic ring.
Heterocyclic ring substitution leads to highly potent compound.
Single benzene ring at N1 is toxic.
Size of group attached to the N is crucial for action and should also impart lipophilicity to the
compound.
N-propyl and higher homologues are active but activity is lost when N-substituent contains more
than 12 or more carbons.

8. Tolbutamide
IUPAC Name - 1-butyl-3-(4-methylphenyl)sulfonylurea
Trade Name - Orniase.
Synthesis -

9. Tolbutamide lowers blood sugar by stimulating the pancreas to secrete insulin and helping the body use
insulin efficiently. It is a first generation sulfonylurea antidiabetic agent.
Metabolism –
Metabolized in the liver principally via oxidation of the p-methyl group producing the carboxyl metabolite, 1-
butyl-3-p-carboxyphenylsulfonylurea.
Absorption –
Readily absorbed following oral administration.
Dosage –
Initial - 1 to 2 g orally once a day or in divided doses through the day.
-Adjust dose based on blood glucose response.
Maintenance dose: 0.25 to 3 g orally once a day or in divided doses through the day.
Maximum dose: 3 g per day.
Half life –
About 7 hours
Side effects –
1. Hypoglycaemia (various symptoms caused by low blood sugar levels, e.g. loss of consciousness) 2.
Weight gain 3. Rare cases of liver damage 4. Drug interactions (especially first-generation drugs):
Increased hypoglycaemia with cimetidine, insulin, salicylates, and sulphonamides.

10. Title Chlorpropamide Glipizide Glimepiride
Structure First Generation Second Generation Third Generation
IUPAC Name 1-(4-chlorophenyl)sulfonyl-
3-propylurea
N-[2-[4-
(cyclohexylcarbamoylsulfamoyl)
phenyl]ethyl]-5-methylpyrazine-2
carboxamide
4-ethyl-3-methyl-N-[2-[4-[(4-
methylcyclohexyl)carbamoylsulfam
oyl]phenyl]ethyl]-5-oxo-2H-pyrrole-
1-carboxamide
Trade name Diabinese Glucotrol Amaryl
Use for the treatment of non-
insulin-dependent diabetes
mellitus (NIDDM).
used to control blood sugar
levels in patients with type 2
diabetes mellitus.
used for the management of type 2
diabetes mellitus (T2DM) to
improve glycemic control.
Metabolism Metabolized in liver metabolized in liver metabolized by CYP2C9
Pharmacokinetic
s
Has high risk of prolonged
hypoglycemia because of
its long half-life of 36hrs .
Readily absorbed from GI.
rapidly absorbed, has a very
quick onset of action and a short
half-life of 4hrs.
very potent and has a longer
duration of action. Completely
absorbed after 1 hr of
administration. Half life 1-2hrs.

11. Title Chlorpropamide Glipizide Glimepiride
Side effects Nausea, loss of
appetite, diarrhea,
Vomiting and weight
gain may occur
low blood sugar, allergic
reaction, digestive
problems such as
nausea, diarrhea, or
constipation.
low blood sugar (hypoglycemia),
headache
Nausea, dizziness, weakness
,unexplained weight gain

12. 2.BIGUANIDES

13. Metformin
IUPAC Name - 3-(diaminomethylidene)-1,1-dimethylguanidine
Metformin is a first line agent for the treatment of type 2 diabetes that can be
used alone or in combination with sulfonylureas, thiazolidinediones, incretin-
based drugs, sodium glucose cotransporter-2 inhibitors, or other
hypoglycemic agents.

14. Mechanism of Action
Activates AMP
activated
protein kinase
(AMPA-PK)
Reduces hepatic
glucose
production
Lowers blood
glucose level

15. Pharmacokinetics –
Absorbed through GI tissue and by small intestine.
Bioavailability – 50-60%
Not metabolized by liver.
Excreted via tubular excretion
Half Life- 2-5hrs.
Uses –
Used in non insulin dependant type 2 DM
Polycystic Ovary Syndrome
Side effects –
GI upset
Acidic acidosis
Impaired absorption of Vit. B12

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