Medicinal Chemistry II

PMC307
Lecture 10
• Oral Antidiabetic Drugs, Part 1

Dr. Sally Tarek Mahmoud, PhD

 1
How Body Maintain Normal
Blood Glucose?
2
How Body Maintain Normal Blood Glucose?

Ingestion of food

3
How Body Maintain Normal Blood Glucose?

Ingestion of food

GIT hormones

GLP-1 & GIP

(Incretins)

GLP-1= Glucagon-like peptide-1

4
α-glucosidase GIP= Gastric inhibitory polypeptide
 How Body Maintain Normal Blood Glucose?

GLUT-2= glucose transporter 5

 How Body Maintain Normal Blood Glucose? Glycogen
Glucose

 Liver
insulin Send
Ingestion of food signals


GIT hormones β α glucagon

α β
GLP-1 & GIP
α-glucosidase (Incretins) 
insulin
α- cells secrete the hormone glucagon. Normal blood glucose
β- cells secrete insulin. level
Homeostasis is restored
Increased glucose uptake by muscle and adipose
tissue 6
How Body Maintain Normal Blood Glucose?

7
Effect of Insulin on the Major Insulin Sensitive
Organs & Tissues

8
2
Diabetes Mellitus
9
 Diabetes Mellitus

 It is a metabolic disorder characterized by hyperglycemia & associated

with impaired fat, carbohydrate, & protein metabolism.

 It is a chronic disease associated with abnormally high level of sugar

glucose that develops when:

* the pancreas is unable to produce insulin.

**or cells cannot absorb the insulin that is available (insulin resistance).
10
Diabetes Mellitus Types

3 Types

11
Diabetes Mellitus Types

Healthy person

Insulin
Deficiency

Insulin
Resistance
12
Diabetes Mellitus Symptoms

13
Diabetes Mellitus Complications

14
Diabetes Mellitus Risk Factors

15
Hemoglobin A1C Test (Gylcated Hemoglobin
Test) for Diabetes

16
Diabetes Mellitus Treatment

17
 3
Major Target Sites of
Oral Antidiabetics
18
 Major Target Sites of Oral Antidiabetics

Skeletal muscle Liver

Adipose
Kidney
tissue

β-cell dysfunction Insulin Hepatic Glucose Glucose absorption Glucose reabsorption

resistance 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

19
 Insulin Secretagogues
β-cell dysfunction

= Stimulation of insulin secretion from functioning β-cells Insulin secretagogues

1- Sulphonylureas
2- Meglitinides
3- GLP-1 agonists
4- DPP-4 inhibitors
Sulphonylureas Meglitinides

GLP-1 Receptor DPP-4

Agonists Inhibitors
20
 Sulphonylureas (SU)
Sulphonylureas M.O.A.
1- Via binding to SUR1 receptor in ATP
sensitive channel (SURs are subunits of the
KATP channels).
2- Induce closure of ATP-sensitive K+
channel.
3- Depolarization then Influx of Ca 2 +.
21
4-  insulin secretion.
 Sulphonylureas M.O.A.

 SUR1 in β-cells of pancreas.

 SUR2B in smooth muscle.

 SUR2A in heart.

Not tissue specific

22
 Sulphonylureas SAR
Sulphonylurea moiety is EFA. Weak acid
No H  activity
OO H
N
HN NH R2R2
NH
RR11 SS CC
O
O O
O
Should be para • Optimum activity 3-7 C.
R1 = p-(β-arylcarboxyamido ethyl) • > 7 C   activity.
 binding affinity. • Lipophilic R2  selectivity to
(2nd generation SU) SUR 1. 23
Sulphonylureas

• 1- Tolbutamide.
First Disadvantages:
• 2- Tolazamide. low potency 
Generation • 3- Chlorpropamide. given in  dose.

They show higher

• 1- Glyburide (Daonil®).
Second activity [smaller
• 2- Glipizide (Minidiab®).
doses] than 1st
Generation • 3- Gliclazide (Diamicron®).
generation.
• 4- Glimepiride (Amaryl®).
24
 1st Generation SU
Tolbutamide Tolazamide
O H O H
N NH CH2CH2CH2CH3 N NH N
H3C S H3C S
O O O O
Butyl azepin
1-butyl-3-(p-tolyl sulfonyl)urea
 The prototype.   potency &  duration than
  potency &  duration. tolbutamide.

25
 1st Generation SU
Tolbutamide Tolazamide
Metabolism : Rapid oxidation

H3C HOH2C HOOC H3C HOH2C HOOC

Active Inactive N
Active Inactive

OH
N

26
Active
 1st Generation SU
Chlorpropamide
O H
N NH CH2CH2CH3
Cl S
Chloro O O Propyl
w-1 w
 The longest duration.
 Contraindicated in elderly & patients with NH CH2CH2CH3

renal problems. Slow

O oxidation

Metabolism : Both are inactive NH CH2CH2CH2

O OH
20% NH CH2CH CH3
excreted unchanged OH 27
O
 2nd Generation SU
Glyburide = Glibenclamide (Daonil®) Glipizide (Minidiab® )
O H H
Chloro S
N N N
H
O N N
O O
Cl O O
N O
H S
OCH3 Pyrazine O H
N N
H

 The Prototype  Short acting (extensive liver

 The most active. metabolism).
 Highly protein bound, long-acting.
 More likely to cause hypoglycemic
episodes due to its longer half-life. 28
 2nd Generation SU
Glyburide = Glibenclamide (Daonil®) Glipizide (Minidiab® )
Metabolism :
Glipizide’s major metabolites are
formed from aromatic hydroxylation &
are reported to be inactive.

29
Glyburide Synthesis

30
 2nd Generation SU
Gliclazide (Diamicron®) Glimepiride (Amaryl® )
O
H Methyl
H HN S N
H
N
N N O
O O O
O O
S
H O H
N N
H
Azabicyclo Pyrroline ring

 Short acting.  Long acting.

 Used for elderly.  High potency.
 Partial inhibition of platelets
aggregation. 31
 2nd Generation SU
Gliclazide (Diamicron®) Glimepiride (Amaryl® )
Metabolism :

HOH2C CH3 HOH2C HOOC

H3C HOOC

Inactive metabolites Active Inactive

32
 Glibenclamide Vs Glimepiride
Glibenclamide Glimepiride
Both are long acting but the incidence of hypoglycemia,
Up to 20% - 30 % 2% - 3 %
Why?
1- Glibenclamide interferes with the normal homeostatic suppression of insulin
secretion in reaction to hypoglycemia, whereas glimepiride does not.

2- Glibenclamide diminishes glucagon secretion in reaction to hypoglycemia,

whereas glimepiride does not. 33
 Meglitinides
Derived from Glyburide
O O H
N NH
Cl S
N
H O O
OCH3

O
O
Cl
N
Meglitinide Prototype
H
OCH3 OH

Benzoic acid derivative 34

 Meglitinides
Repaglinide (Novonorm®) Nateglinide (Starlix® )
H3C O OH
O
H O
H3C N O N
H
OH
N
OC2H5

 Not tissue specific  Selective to SUR1.

(binds to SUR1, SUR2A, B)
More potent 10 times > glyburide.
Rapid onset should be taken during meals.
Short duration (extensive metabolism)  With lower side effects
35
(lower dangerous hypoglycemia)
 Incretin effect

 1st described in 1960.

 Researchers observed that administration of an oral glucose load led to
significantly greater plasma insulin response when compared to i.v.
glucose load.

Oral glucose i.v. glucose

� insulin  insulin
36
 What are Incretins?

 Peptides Hormones produced by GIT in response to incoming

nutrients  stimulate insulin secretion.

INCRETIN= Intestinal + seCRETion of INsulin

37
 Incretins Hormones
2 Hormones:

1) Glucagon-like peptide-1 (GLP-1)

Most potent in stimulating insulin secretion.

2) Glucose-dependent insulinotropic polypeptide (GIP)

(Gastric inhibitory polypeptide).
38
 Actions of GLP-1

Beneficial effects of GLP-1

▰ Stimulation of insulin secretion.

▰ Suppression of glucagon secretion.

▰ Slowing of gastric emptying.

▰ Induction of a sense of satiety & fullness.

▰ Reduction of hepatic glucose output.

39
Actions of GLP-1

40
In Type II Diabetes

GLP-1  GIP 
Type II diabetes patients are resistant to its
action
(high blood level)

GLP-1 agonists making it a less attractive therapeutic target.
41
The Problem

GLP-1 is rapidly broken down by the DPP-IV enzyme

Very short half-life in plasma (1 - 2 minutes).

Limited use as a therapeutic agent.

42
 DPP-4 (Dipeptidyl peptidase-4)

▰ The enzyme that rapidly inactivates GLP-1.

DPP-IV DPP-4 selectively cleaves two amino acids from peptide.

His Ala Glu Gly Thr Phe Thr Ser Asp Glu Gly Thr Phe Thr Ser Asp
Val Val
Ser Ser
Lys Ala Ala Gln Gly Glu Leu Tyr Ser DPP-IV Lys Ala Ala Gln Gly Glu Leu Tyr Ser
Glu Glu
Phe Phe
Ile Ala Trp Leu Val Lys Gly Arg Gly Ile Ala Trp Leu Val Lys Gly Arg Gly

GLP-1 Active GLP-1 Inactive 43

 Incretin Based Therapy

Two new classes of agents

1) GLP-1 agonists.
 Exenatide.
 Liraglutide.

2) DPP-IV inhibitors.
 Vildagliptin.
 Saxagliptin.
 Sitagliptin.
44
 GLP-1 agonists

Exenatide (Byetta®) subcutaneous injection

 Incretin mimetic.
 A synthetic version of Exendin‐4, a hormone found in the saliva of the Gila
monster lizard.
 GLP-1 receptor agonist but resistant to DPP-4 (longer duration t1/2 = 3
hours).
 39 amino acid peptide. It has 50% sequence homology with native GLP‐1
with the substitution of glycine instead of alanine in N‐terminal position. 45
 GLP-1 agonists

Exenatide (Byetta®) subcutaneous injection

Human GLP-1 46
 GLP-1 agonists
Liraglutide
 Liraglutide is an analogue of endogenous human GLP‐1 with 97% of
sequence homology.
 Amino acid Lysine is replaced by arginine.
 Palmitoyl acid binds reversibly to plasma albumin that prevents its
degradation by DPP‐4 and depot formation at the injection site with slow
dissolution is responsible for its prolonged duration of action.
47
 GLP-1 agonists

Liraglutide

Human GLP-1
48
 DPP-4 Inhibitors (Gliptins)
DPP-4 Inhibitors M.O.A.

They inhibit the action of DPP4 (which degrades GLP-1, GIP & convert them to
inactive form ).
49
DPP-4 Inhibitors

Gliptins “Incretin Enhancers"

Substrate-like Non Substrate-like

inhibitors inhibitors

Vildagliptin (Galvus®) Sitagliptin (Januvia®)

Saxagliptin (Onglyza®) 50
 Substrate-like Inhibitors Binding with the Enzyme

S2 pocket

Protonated amino gp forms a R N • Small lipophilic.

H-bond network with a N • Contains Ser OH
negatively charged region of H
O (serine AA).
the protein, Glu205, Glu206 &
Tyr662. (1ry or 2ry amine). N
S1 pocket
• CN forms reversible covalent bond with the serine OH  so nitrile is critical to achieve
potent activity.
• Since the good fit of the ring with the hydrophobic S1 pocket is very important for high
51
affinity  Only minor changes on the pyrrolidine ring can be tolerated.
 One Major Problem

 DPP-4 inhibitors are not very stable

compounds due to intramolecular cyclization.

 Trans‐rotamers are more stable then cis‐rotamers.

Cis‐rotamers undergo intramolecular cyclization.

Thus, preventing this conversion will increase stability


No intramolecular cyclization
+ Inactive
52
More selective over different DPP enzymes
 Substrate-like Inhibitors

Vildagliptin (Galvus®)
 The adamantyl group
 steric bulk.
 slowed intramolecular cyclization. (3-hydroxyadamantan-1-yl)amino]acetyl)-
pyrrolidine-2-carbonitrile
  chemical stability.
 Electrophilic gp (CN)  forms covalent bond with active site serine & reversibly
inactivate it  Covalent imidate complex (slow hydrolysis)   activity.
 Highly Selective DPP-4 inhibitor.
 Well tolerated. 53
 Substrate-like Inhibitors

Saxagliptin (Onglyza®)

Vildagliptin

4,5-methano substitution of the pyrrolidine ring

additional increase in stability by preventing intramolecular cyclization. 54
 Non-Substrate-like Inhibitors

 They are non-covalent inhibitors.

 Have an aromatic ring that occupies the S1-pocket, instead of the
pyrrolidine mimetic.

55
 Non-Substrate-like Inhibitors

Sitagliptin (Januvia®)

Six F
The trifluoromethyl group
The trifluorophenyl group of the triazolopiperazine
occupies the S1-pocket group interacts with the
side chains of residues
Arg358 and Ser209
NH2 forms H-bonding network

56