Oral Hypoglycemic Agents Medicinal Chemistry

ORAL HYPOGLYCEMIC AGENTS MEDICINAL CHEMISTRY
1. 1. Referred to as “Anti-diabetic medication”. Drugs used in the treatment of diabetes

mellitus by lowering the blood glucose level. These are administered orally and are
thus also called as oral hypoglycemic agents or oral ant hyperglycemic agents. There
are different class of antidiabetic drugs and their selection depends on nature of diabetes
,age ,and situation of the person as well as other factors
2. 2. Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia
resulting from defects in insulin secretion, insulin action or both. There are 2 major types
of DM • Type 1- Immune β-cell destruction or idiopathic, leading to absolute insulin
deficiency • Type 2- Insulin resistance with relative insulin deficiency or insulin
secretory defects with insulin resistance
3. 3. Other types include • Gestational Diabetes-Diabetes diagnosed in the second or third
trimester of pregnancy that is not clearly shown diabetes • Specific types of diabetes due
to other cause-Neonatal diabetes, maturity –onset diabetes of the,disease of the exocrine
pancreas and drug or chemical induced diabetes.
4. 4. SULPHONYLUREAS NON-SULPHONYLUREAS (MEGLITINIDES)
THIAZOLIDINEDIONES BIGUANIDE ALPHA-GLUCOSIDASE INHIBITORS
5. 5. Contain sulphonyl and urea group The sulphonyl portion is very water soluble,it has
am acidic amine and oxygen atoms for good hydrogen bonding R1 and R2 are very
lipophilic and account for differences in overall potency,metabolism,duration and
routes of elimination Overall drugs tend to be lipophilic and ionised at body pH They
are weak acids with a pKa equivalent 5-6 Second generation much more lipophilic than
the first and hence more potent They stimulate secretion of insulin from the functioning
β-cells of the intact pancreas Sulphonylureas are similar in chemistry to the
sulphonamides and thus potentially share toxicities and allergies
6. 6. SAR:- R1 Must be lipophilic Must have an aromatic ring next to the sulfoxide
groups have a phenyl ring Should have a substitutent at the para position. Methyl,
amino, acetyl, chloro, bromo, metyithio and trifluorometyl enhance hypoglycemic
activity. The larger, more complex, para substituents comprise the 2nd generation. The
ethylcarboxamide appears to be very potent in these drugs which may be due to the
distance from the carboxamide nitrogen to the sulfonamide nitrogen and how its binds to
the receptor. R2 Must be lipophilic Has some size constraints: N-metyl is inactive, N-
ethyl is low active, N-dodecyl and above are inactive N-propyl to N-hexyl are the most
potent
7. 7. TOLBUTAMIDE CHLORPROPAMIDE TOLAZAMIDE ACETOHEXAMIDE
8. 8. 1st Generation:- 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 hydroxylationof para methyl substituents followed by oxidation to
the acid. In Chlorpropamide the para chloro protect from oxidation and thus has a
longer duration than tolbutamide. Also increases lipid solubility to increase potency.
Tolazamide has a cyclic substituents that makes it approximately equal to
chlorpropamide in potency even though the para substituents is the same as tolbutamide.
Oxidized quickly as with tolbutamde, 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
4th position on the hexane ring is also hydroxylated. Duration is similar to tolazamide.
9. 9. 2nd Generation:- Due to their larger molecular size, biliary excretion becomes
important. Glyburide and Glipizide are hydroxylated at the 3rd and 4th position on the
cyclohexyl ring. Some metabolites are active so duration is longer than parent
compound. Glimepride, sometimes referred to as 3rd generation, is most potent of all
sulfonylureas. The cyclohexyl metyl is hydroxylated then oxidized to the acid.
10. 10. The meglitinide are nonsulfonylurease oral hypoglycemic agents used in the
management of type 2 diabetes (NIDDM). These agents tends to have rapid onset and
short duration of action. Mechanism of action is similar to that of sulfonylurease.
There are two major difference between these two classes -- Meglitinide cause must
faster insulin production than sulfonylurease -- Effects of metaglinides do not last as long
as the effect of sulfonylurease -- The effect of these class appear to last less than one hrs
while sulfonylurease continue to stimulate insulin productin for several hrs. As a result
meglitinide should be taken 5 to 10 mins before meal. There is less risk of
hypoglycemia due to short duration of action. Repaglinide excreted less than 0.2% by
kidney which may be advantage for elderly patient who are renally impaired.
11. 11. Repaglinide Nateglinide
12. 12. The thiazolindione represent a novel nonsulfonylurease class of hypoglycemic agents
for the treatment of NIDDM. Much like the sulfonylurease, the use of these agents
requires a functioning pancreas that can successful secrete insulin from β-cell. The
thiazolindindione are highly selective agonist for the peroxisome proliferator –activated
receptor-gamma(PPARG), which is responsible for improving glycemic control,
primarily through the improvement of insulin sensitivity in muscle and adipose tissue.
13. 13. 1)Rosiglitazone:- 2)Pioglitazone:-
14. 14. Metformin:- IUPAC:-N,N-dimethylimidodicarbonimidic diamide These class of
agents is capable of reducing sugar absorption from the gastrointestinal tract. Also,
they can --decrease gluconeogenesis --increasing glucose uptake by muscle and fat
cells. These agents unable to stimulate the release of insulin from the pancrase.
15. 15. The enzyme α-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 these enzyme allows less dietary carbohydrates to be available for
absorption and, in turn, less available in the blood following a meal.
16. 16. 1)Acarbose:- It is naturally occurring oligosacharide, which is obtained from the
microorganism Actinoplanes utahensis. It has high affinity for α-glucosidase enzyme
due to its oligosacharides nature.
17. 17. 2)Miglitol:- It is chemically known as 3,4,5-piperidinetriol It is soluble in water
with pka 5.9 In chemical strcture, these agent is very similar to sugar, with the
heterocyclic nitrogen serving as isosteric replacement of the sugar oxygen. This feature
allows recognition by the α-glucosidase as a substrate. This result in the competative
inhibition of enzyme and delays the carbohydrates from the gastrointestinal tract.
18. 18. THANK YOU........

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ORAL HYPOGLYCEMIC AGENTS MEDICINAL CHEMISTRY

1. 1. Referred to as “Anti-diabetic medication”. Drugs used in the treatment of diabetes

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