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Transcript
Prodrugs
Medicinal Chemistry I
1
Prodrugs
Are inactive compounds converted to the active
form in vivo.
 Useful for drugs with undesirable physicochemical
property.
2
Undesirable Properties
• Physical Properties:
a) Poor aqueous solubility
b) Low lipophilicity
c) Chemical instability
d) Acid Sensitivity
e) Poor Membrane Permeability (poor absorption)
f) Toxicity (non-selective bioactivity)
g) Bad Taste
h) Short Duration of Action
i) Non-site specific
3
Prodrugs activation mechanisms
• Variety of mechanisms by which prodrug can be
converted into active drug:
1. Metabolizing enzymes (phosphotase, esterases,
peptidase)
• Interpatient variable
2. Chemical activation (Hydrolysis, decarboxylation, light
activation)
• Stability issues
3. Mixture of both
• Two important points:
1. The prodrug should be effectively converted to the active form
once absorbed in the blood.
2. Cleavable groups are non toxic.
4
Not all prodrugs are activated by metabolic
enzymes.
Photodynamic therapy involve the use of an
external light to activate prodrugs.
Prodrugs classification
• Can be classified into three categories:
1. Carrier-linked prodrugs
- Carrier-linked prodrugs are drugs that have been
attached through a metabolically labile linkage to
another molecule, the so-called promoiety, which is
not necessary for activity but may impart some
desirable property to the drug
6
Prodrugs classification
2. Mutual prodrugs
- In this type, both the drug and the
carrier has activity
7
Produrgs classification
3. Bioprecursor prodrugs
- contain no promoiety but rather rely on metabolism
to introduce the functionality necessary to create an
active species
8
Carrier-linked prodrugs
Prodrugs functional groups
9
Prodrugs functional groups - Esters
 The most common type of prodrug because of the ease with
which the ester can be hydrolyzed or formed.
 Esterase enzymes present in plasma and other tissues that are
capable of hydrolyzing a wide variety of ester linkages
 Can add lipophilicity or hydrophilicity to the drug
 Increasing lipophilicity of the compound may yield a number
of benefits, including increased absorption, decreased
dissolution in the aqueous environment of the stomach,
longer duration of action, and reducing bad taste
10
Improve membrane permeability
• Problem: - Epinephrine is poorly absorbed through eye tissues
- Catechols are unstable
• Solution: The increased lipophilicity relative to epinephnine allows the
drug to move across the membrane of the eye easily and achieve higher
intraocular concentrations
• The steric bulk of pivalic acid slows down the hydrolysis
11
Improve Membrane Permeability
 Ampicillin is poorly absorbed from the GI tract
(~30% absorbed)
WHY???
 The carboxylic acid functional group (COOH):
 Binds the drug to a receptor via ionic or
hydrogen bonding.
 An ionizable group may prevent drug from
crossing a fatty cell membrane.
Solution:
 Convert the acid function to an ester moiety.
 The less polar ester can cross fatty cell
membranes.
 The ester group will be hydrolyzed back to the
free acid by the esterase in the blood.
12
Ampicillin activation In Vivo
13
Masking bad taste
• Problem: Water soluble drugs when dissolve in the mouth
could lead to bad taste
- This cause low compliance (pediatric)
• Solution: A prodrug with reduced water solubility does not
dissolve to any appreciable extent in the mouth and,
therefore, does not interact with taste receptors.
14
Prodrugs for stability
• Problem: propanolol undergo extensive first
pass metabolism (glucuronidation)
• Solution: adding ester group on the alcohol
will protect it from metabolism
Prodrugs for stability
Increasing hydrophilicity
• Increase the water solubility of drugs, making them more
suitable for parenteral or oral administration when high water
solubility is desirable
Clindamycin Phosphate
17
Improve membrane permeability
Peptide carrier systems
Improve membrane permeability
Peptide carrier systems
Prodrug
Protein Carrier in BBB (Blood Brain Barrier)
19
Drugs with amine moiety
• The amide derivative is not a suitable choice
in most of the case (WHY?)….Stable bond
toward hydrolysis compared to the ester
bond.
Drugs with amine moiety
Prodrug to increase lipophilicity
21
Drugs with amine moiety
Prodrugs to increase water solubility
Prolong The Activity
Diazepam
Prodrug
O
•Sustained Action
•N-demethylation Metabolism
Hexobarbitone
Me
N
O
NH
O
Me
23
Prodrugs to mask toxicity and side effects
Cyclophosphoramide for phosphoramide mustard
(anticancer agent)
NH
O
P
O
1. Cyt P450
2. Phosphoramidase
Cl
(liver)
H2N
Cl
P
HO
N
O
N
Cl
Cl
Cyclophosphoramide
Phosphoramide mustard
•
•
•
Non toxic
Orally active
Alkylating agent
Azo prodrugs from amine
25
Prodrugs used to target drugs
Example:
Hexamine
N
N
N
N
•
•
•
•
Stable and inactive at pH>5
Stable at blood pH
Used for urinary infections where pH<5
Degrades at pH<5 to form formaldehyde (antibacterial agent)
Bioprecursor prodrugs
• Bioprecursor prodrugs mostly use either oxidative or reductive activation
reactions.
• The main activation pathways are:
1) Proton activation.
2) Hydrolytic activation
3) Elemination activation
4) Oxidative activation
5) Reductive activation
6) Nucleotide activation
7) Phosphorylation activation
8) Sulfation activation
9) Decarboxylation activation
27
Reduce toxicity
Nabumetone
28
Reduce toxicity
Idoxuridine phosphorylation
29
Most other antiviral requires the same
activation mechanism
N
HO
N
N
N
N
PO
Vi ral
NH2 thymidi ne
kinase
Penciclovir
OH
N
N
N
N
NH2
P P PO
N
N
N
NH2
Cell kinases
OH
OH
30
Proton Pump Inhibitor Activation
Omeprazole
31
32
Bioluminescent
Red Tide
33
34