Download pro-drugs

Xenobiotic or Drug Metabolism
Xenobiotic : Any compound entering into organism
from outside such as:
•Synthetic intermediates
•Industrial Chemicals
•Drugs
•Cosmetics and Dyes
•Food additives
•Air pollutants
These xenobiotics can be metabolised in the body
to new products «metabolites» by specific enzymes
What is the aim of drug metabolism?
Increasing polarity and elimination
Decreasing toxicity especially with Phase II reactions
What is the main place for drug metabolism reactions ?
Liver
What is the difference between in vivo and in vitro drug
metabolism studies?
In vivo studies are carried out in intact animals,
the final phase of the metabolism in body fluides (phase II) can be established.
In vitro studies are carried out liver preparations (microsomes)
The intermediate products of the metabolism (phase I) can be established.
Why drug metabolism important in
terms of medicinal chemistry ?
• Pro-drugs may be designed.
• Pharmacologically active metabolites can be
manufactured as a potential drug.
• If toxic metabolites are established, then the
drug may be prohibited.
1st Phase Reactions
• Oxidation
• Reduction
• Hydrolysis
Substrate molecule changes and polarity increases
and it will have a structure which is suitable for
Phase 2 reactions but the toxicity may increase.
PRO-DRUGS
These drugs are not active but their metabolites
are active following enzymatic metabolism.
Design of pro drugs may be
neccessary in the following situations:
Physico-chemical, biopharmaceutical and
pharmacokinetic problems occur in the
formulation and delivery of drugs.
for example bad taste and odour, solubility
problems
Urotropine (hegzamethylenetetramine)
(CH2)6N4
HCHO
+
NH3
formaldehyde (active)
OCOCH3
hid.
OH
+
COOH
Aspirin
(pro-drug)
COOH
Salisylic acid
(active)
CH3COOH
Chloramphenicol palmitate is given for masking poor taste and odour of
chloramphenicol
To increase the liphophilicity of ampicillin in gastrointestinal system
pivampicillin ester pro-drug is prepared:
Functional Group
These are the groups consisting of elements such as O, N, S,
and X (halogene). They give the distinct chemical,
pharmacological, toxicological activities (function) to the
molecule.
Alcohols
•
•
•
Weak base to strong acids
Weak acid to strong bases
OH group is a polar «water soluble» group
Phenols
•
•
3
3
Weak acidic
Water soluble
OH
C OH
OXIDATION OF CARBON
CH3
Toluene
CH2OH
alcohol
CHO
aldehyde
COOH
carbocylic acid
ETHERS
•neutral and inert
•insoluble in water
3
5
C O C
ALDEHYDES and KETONES
•neutral molecules
•aldehydes are more reactive than ketones
•water solubility decreases with the increasing C number
•aldehydes are more reactive than ketones
CCC
C
H
O
Aldehyde
(carbonyl group at the end
of the molecule)
3
6
CCC
C
CC
O
Ketone
(carbonyl group in the middle
of the molecule)
CARBOXYLIC ACIDS and
THEIR DERIVATIVES
•Carboxylic acids are polar groups
•Their salts are much more soluble in water
•Esterler are less polar compared to the
corresponding carboxylic acids
R-COOH
R-COOMe
R-COOR1
Me = Metal ie. sodium, potassium
3
7
FUNCTIONAL GROUPS WITH NITROGENE
• Amine
• Imine
• Azo
• Amide
• Nitro and nitroso
H
R
tersiyer amin
N C
R
nitro
NO2
C
C C
C
N
primer amin
H
H
N
sekonder amin
R
C C N C
O
amid
C C N
imin
C
C N N
azo
HYDROLYSIS
It is a common decomposition reaction with water for the following functional groups:
•
•
•
•
•
•
•
4
0
Amide
Ester
Epoxide
Sulfonamide
Imine
Hydrazone
Hydrazide
R CH CH2
O
R-SO2NH2 + H2O
R CH
CH2
OH
OH
R-SO3H
+
NH3
Sülfonik asid
R-N=CH-R + H2O
R-NH2
R-CHO
+
pr. amin
H2N-N=CH-R + H2O
aldehid
H2N-NH2
+
hidrazin
H2N-NH-C-R + H2O
O
H2N-NH2
hidrazin
4
1
+
R-CHO
aldehid
R-COOH
asid
OXIDATION OF AMINES
H
H
R N
R N
H
Primer amin
OH
Primer hidroksilamin
R
R N
H
Sekonder amin
R
R N
R
Tersiyer amin
4
2
R
R N
OH
Sekonder hidroksilamin
R
R N OR
+
N-oksit
AMINES and AMIDES
R N
H
H
Amines are basic compounds
Primary amines are much more soluble and
basic than secondary and tertiary ones.
Amides are soluble in water
Amides are neutral because of the carbonyl
group.
4
3
O
R C N
H
H