PHAR-754

MEDICINAL CHEMISTRY

ANTIDIABETIC AGENTS

SPRING 2007

1
SULFONYLUREAS

1. Tolbutamide (Orinase)
2. Chlorpropamide (Diabinase)
3. Tolazamide (Tolinase)
4. Acetohexamide (Dymelor)
5. Glipizide (Glucotrol, Glucotrol-XL)
6. Glyburide (Micronase, Diabeta)
7. Glimepiride (Amaryl)
8. Gliclazide (Diamicron)

O O
H H
General Formula: R1 S N C N R2

Drug Name R1 R2

Tolbutamide H3C C4H9

(Orinase)
Chlorpropamide Cl C3H7
(Diabinese)

Tolazamide N
H3C
(Tolinase)

O
Acetohexamide H3CC
(Dymelor)

N
Glipizide H3C CONH(CH2)2
(Glucotrol)
N

Cl
Glyburide
(Glibenclamide, CONH(CH2)2
Micronase,
Diabeta, Glynase)
OCH3

Gliclazide H3C N
(Diamicron)

H3C
Glimepiride CH3
N CONH(CH2)2
(Amaryl)
C2H5
O

2
Structure Activity Relationships:

R1 (see figure on p. 2) should be a p-substituted benzene. A wide variety of substituents

are possible. But methyl groups on aromatic rings are usually susceptible to metabolic
enzymes. They can be oxidized to carboxylic acids, which can be quickly eliminated from
the body.
These susceptible groups can sometimes be replaced with groups that are more stable to
oxidation in order to prolong the lifetime of the drug. For, example, the methyl group of
tolbutamide was replaced with a chlorine atom to give chlorpropamide, which is much
longer lasting.

R2 should be lipophilic with 3 – 6 carbons optimal (in case of aliphatic chain such as in
tolbutamide and chlorpropamide). A single CH3 shows no activity and C12 shows a loss of
activity relative to intermediate length chains. If an alicyclic ring is used, the number of
carbons can be increased.

SAR of Glyburide (glibenclamide)

important for activity cyclohexyl ring

important for selectivity for SUR1

important for activity O

O O
S
O N N
H H
Cl the acyclic analogs showed
N markedly reduced activity
H compared to glibenclamide

OCH3

replacement of the methoxy group with methyl Glyburide

resulted in the decrease of activity, indicating the (Glibenclamide)
requirement for an electronegative atom at this
position

3
MEGLITINIDES (METAGLINIDES)

1. Repaglinide (Prandin)
2. Nateglinide (Starlix)

O OH

N O
H

N repaglinide

COOH O

N
H

nateglinide

4
STRUCTURE ACTIVITY RELATIONSHIPS OF SULFONYLUREAS AND MEGLITINIDES

Dose response relationships for inhibition of beta cell and cardiac type KATP currents by
sulfonylureas and metaglinides. Kir6.2/SUR1 and Kir6.2/SUR2 currents are inhibited by
increasing concentrations of sulfonylureas and metaglinides.

5
 O O O
S
N N CH3
H H
H3C tolbutamide

O O O
S CH3
N N
H H
Cl chlorpropamide

O OH relatively
C O selective
for SUR1-type
channels
N
H
nateglinide

O OH
C O
H
N

mitiglinide H

O O O
S
O N N
H H
Cl
N
H inhibit channels
glibenclamide
OCH3 containing
CH3 either SUR1 or
O O O SUR2.
S
O N N
H H
H3C
N N
H
glimepiride
C2H5 O

6
The reversibility of different sulfonylureas and metaglinides was measured on Kir6.2/SUR1
and Kir6.2/SUR2A currents expressed in Xenopus oocytes. Currents are shown in
response to repeated voltage ramps from –110 to +110 mV.
Most drugs that have only one active group (either a sulfonylurea or a non-sulfonylurea)
are rapidly reversible over a recording period of less than 30s. This group includes
tolbutamide, chlorpropamide, gliclizide, and meglitinide. By contrast, drugs that posses
both sulfonylurea and non-sulfonylureas moieties (glibenclamide and glimepiride) are
effective irreversible in patch clamp experiments (measured over several minutes). An
exception to the rule, repaglinide, which does not posses a sulfonylurea group, yet is very
difficult to wash off KATP channels in membrane patches.

7
BIGUANIDES

1. Phenformin (withdrawn) caused lactic acidosis.

2. Metformin (Glucophage, Glucophage XR)
3. Metformin + Glyburide (Glucovance)

NH NH
H3C
H
N C N C NH2
H3C
metformin

NH NH2 NH NH2
H3C H3C
H H
N C N C NH2 N C N C NH2
H3C H3C

NH2 NH NH NH2
H3C H3C
N C N C NH2 N C N C NH2
H H
H3C H3C

NH2 NH NH2 NH
H3C H3C
H H
N C N C NH2 NH C N C NH2
H3C H3C

Resonance stabilizes positive charge. With a pKa of 12.4, metformin has nearly a
permanent positive charge.

Phenformin is much more lipophilic than

metformin. Potency: phenformin > metformin.
NH NH However, lipophilicity may correlate to its
H toxicity (lactic acidosis). It may bind more
N C N C NH2 strongly to mitochondrial membranes and
H inhibits mitochondrial oxidative phosphorylation
phenformin (inhibits oxygen consumption) causing a shift to
anaerobic glycolysis.

8
THIAZOLIDINEDIONES (GLITAZONES)

1. Pioglitazone (Actos)
2. Rosiglitazone (Avandia)
3. Troglitazone (Rezulin) - withdrawn
O

H3C
NH
S
N O
O
pioglitazone

CH3
NH
N S
O

N O
rosiglitazone

9
AMINOCYCLITOLS (α-glucosidase inhibitors)

Acarbose (Precose)
Voglibose (Basen)
Miglitol (Glyset)
OH

HO
H3C
O
HO N
H HO CH2OH
OH OH O
O
HO
OH CH2OH
O
O
acarbose HO
OH OH
Acarbose is produced by the soil bacterium Actinoplanes sp.
Its strong inhibitory activity against α-glucosidases is widely attributed to the enhanced
binding of the core aminocyclitol valienamine, whose half-chair conformation mimics the
substrate distortion expected in the oxocarbonium ion transition state. In addition, the
adjacent N-linked glycosidic bond prevents enzymatic hydrolysis. This amino linkage forms
salt link to the acidic group of the glucosidases, which probably contributes significantly to
the unusually tight binding of the inhibitor with the enzymes.

Miglitol is a second-generation alpha-glucosidase inhibitor derived from 1-

desoxynojirimycin. In contrast to acarbose, miglitol is almost completely absorbed in the
small intestine.

OH

HO OH
N

HO
OH
miglitol

10
 Amylase
hydrolysis site

OH OH OH OH OH OH OH
O O O O O O O

O HO O HO HO O HO HO O HO HO O HO HO O HO HO O HO O
HO HO carbohydrate

–4 –3 –2 –1 +1 +2 +3

Asp-174 (Nucleophile) Asp-174

OH –O O OH O
OH O
O O OH
O
O
O HO HO O O
HO HO O HO HO O HO O
HO
H H
O O
O O

Glu-200 (Acid/Base)
Glu-200

Asp-174

O OH
O
OH
O O HO
HO HO O

O HO HO
O H
H

–
O O

Glu-200

Amylase
hydrolysis site

OH
OH OH
H3C O O O
OH N OH acarbose
HO HO O HO HO O HO HO
HO H HO
–1 +1 +2 +3

11