Medicinal Chemistry II

PMC307
Lecture 11
• Oral Antidiabetic Drugs, Part 2

Dr. Sally Tarek Mahmoud, PhD

 Major Target Sites of Oral Antidiabetics

Skeletal muscle Liver

Adipose
Kidney
tissue
β-cell dysfunction
Insulin Hepatic Glucose Glucose reabsorption
resistance overproduction Glucose absorption
Insulin secretagogues Insulin sensitizers
1- Sulphonylureas 1- Biguanides
2- Meglitinides 2- PPAR agonist New drugs
3- GLP-1 agonists 1- α-glucosidase inhibitors
4- DPP-4 inhibitors 2- Biguanides SGLT-2 inhibitors

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 Insulin Sensitizer Skeletal muscle
Adipose
Liver

tissue

Insulin Hepatic Glucose

 Improve glucose utilization without stimulating pancreatic resistance overproduction
Insulin sensitizers
insulin secretion. 1- Biguanides
2- PPAR agonist
 They are only active in presence of insulin.

Biguanides PPAR Agonists

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 Biguanides

Metformin (Cidophage®, Glucophage®)

SAR NH
NH H

Phenformin Buformin N-1,1-dimethyl biguanide

 Toxic derivatives due to lactic acidosis.

 Phenformin inhibits lactate oxidation &  lactate production.

 Phenformin, Buformin  withdrawn from the market. 4
Metformin M.O.A.

NO effect on insulin secretion


Metformin does not cause hypoglycemia

(Antihyperglycemic Drug)

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 Metformin Uses

 Metformin is the first drug of choice for the management of type II

diabetes.
 Either alone or in combination.
 Glucose-lowering extent of metformin is additive when used in
combination with every known hypoglycemic drug.
 Other benefits:
weight loss &  plasma triglycerides. 6
 Metformin

Metabolism
Excreted in urine as unmetabolized drug.

Contraindications

Renal impairment & hepatic disease.

Side effects
Minimal risk of lactic acidosis. 7
 Peroxisome Proliferators‐Activated Receptors (PPAR) Agonists

Peroxisome Proliferators - Activated Receptors

 Nuclear receptors.
 Induce proliferation of peroxisomes
(organelles involved in fatty acid oxidation).

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 PPAR

How??

Endogenous ligands for these receptors are free fatty acids.

1- When activated , the receptor binds to DNA only as a dimer with the
retinoid X receptor, RXR (another nuclear receptor).

2- Increase transcription of specific genes & decrease transcription of others.

= Regulate gene expression 9

 PPAR

The main effect of expression & repression of specific genes is

Encode for protein formation & Proliferation of peroxisome  Fatty acid oxidation.
  storage of fatty acids in adipocytes or use.
  amount of fatty acids present in circulation.
 As a result, cells become more dependent on the oxidation of carbohydrates, more
specifically glucose, in order to yield energy for other cellular processes.
  glucose uptake by cells of muscle & adipose tissue.
  insulin sensitivity. 10
PPAR are 2 Subtypes

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 S
Thiazolidine-2,4-diones (Glitazones) M.O.A. O
O N
H
 Muscle, fat, & liver cells have receptors called "peroxisome proliferator-
activated receptor-gamma (PPAR γ )" in their nucleus.
 Glitazones stimulate PPAR γ nuclear receptors  activate a number of
insulin-responsive genes  the cell becomes more sensitive to the
effects of insulin.
= Thiazolidinediones are PPARs γ agonists   insulin resistance.
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 Thiazolidine-2,4-diones (Glitazones)

Pioglitazone
N O O
NH
O
S
Essential groups
H
O N O
Rosiglitazone S
O

N
N 13
 Thiazolidine-2,4-diones (Glitazones)
N O O
NH
Pioglitazone (Hi Glitazone®) O
S

 Pioglitazone doses are sufficiently lower (by 10-fold) than that needed with
rosiglitazone  No hepatotoxicity.
Metabolism

All are active metabolites. 14

 Major Target Sites of Oral Antidiabetics

Skeletal muscle Liver

Adipose
Kidney
tissue
β-cell dysfunction
Insulin Hepatic Glucose Glucose reabsorption
resistance overproduction Glucose absorption
Insulin secretagogues Insulin sensitizers
1- Sulphonylureas 1- Biguanides
2- Meglitinides 2- PPAR agonist New drugs
3- GLP-1 agonists 1- α-glucosidase inhibitors
4- DPP-4 inhibitors 2- Biguanides SGLT-2 inhibitors

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Glucose Absorption

Glucose absorption

1- α-glucosidase inhibitors
2- Biguanides
α-Glucosidase
Biguanides
Inhibitors

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 α-glucosidase Inhibitors

Acarbose (Glucobay®)

 Acarbose is a pseudotetrasaccharide of
microbial origin, obtained form
fermentation of Actinomyces.

 N atom binds to α‐amylase more tightly than the natural substrate 

potent inhibitor. 17
 Acarbose M.O.A.

Acarbose (Glucobay®)
 Acarbose inhibits α-glucosidase enzymes (maltase, amylase, sucrase) in
GIT .
 Delays absorption of complex CHO & simple sugars by moving these
undigested disaccharides into the distal sections of small intestine & colon.
 the result is prevention of glucose production.
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 Acarbose Side effects

Acarbose (Glucobay®)
Flatulence
Caused by fermentation of undigested sugars in the large bowel by intestinal
microflora.

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 Major Target Sites of Oral Antidiabetics

Skeletal muscle Liver

Adipose
Kidney
tissue
β-cell dysfunction Insulin
resistance Hepatic Glucose Glucose absorption Glucose reabsorption
overproduction

Insulin secretagogues Insulin sensitizers

1- Sulphonylureas 1- Biguanides
2- Meglitinides 2- PPAR agonist New drugs
3- GLP-1 agonists 1- α-glucosidase inhibitors
4- DPP-4 inhibitors 2- Biguanides SGLT-2 inhibitors

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 Glucose Reabsorption
Kidney

Sodium Glucose Cotransporter 2 Inhibitors Glucose reabsorption

(SGLT-2) (Gliflozins)

New drugs
 In hyperglycemia, the kidneys may play an SGLT-2 inhibitors
exacerbating role by reabsorbing excess glucose 
chronic hyperglycemia.

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 Sodium Glucose Cotransporter 2 (SGLT-2) Inhibitors
(Gliflozins)

SGLT-2 Inhibitors M.O.A.

 In healthy individuals, the vast majority
of the glucose filtered by the kidney is
reabsorbed by SGLT-2 in proximal
convoluted tubule & the remaining
glucose is reabsorbed by SGLT-1.

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 SGLT-2 Inhibitors M.O.A.

 SGLT-2 is a transporter found in the

brush border of the proximal tubule.
 It is a mediator of glucose
reabsorption in the kidneys.

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SGLT-2 Inhibitors M.O.A.

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 SGLT-2 Inhibitors M.O.A.

SGLT-2 inhibitors exert their effects by causing the kidneys to excrete

glucose into the urine.

Independent of insulin secretion.

Low incidences of hypoglycemia with minimal side effects.

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 SGLT-2 Inhibitors

Canagliflozin HO
O
H
S F

HO OH
OH
Cl O

Dapagliflozin HO
O

HO OH
OH
Cl O
Empagliflozin O
O
HO

HO OH
OH 26