Drug Design: Pro Drugs

Question 0

How can metabolism of a drug compound be used to our advantage?

Answer 0

We can design a drug that has the awkward functionality masked.
Metabolic enzymes in the bloodstream or liver can unmask it, revealing the active drug

Question 1

What does pharmacokinetic drug design involve?

Answer 1

Altering molecular structure to improve metabolic stability, poor permeability and toxicity

Question 2

What are pro drugs?

Answer 2

Inactive compounds that yield an active compound upon metabolism in the body

Question 3

What are the two main groups of prodrugs?

Answer 3

Carrier prodrugs

Bio precursor prodrugs

Question 4

What are carrier prodrugs?

Answer 4

The active drug is linked to a removable carrier
The carrier species has the improved properties such as lipophilic for membrane permeability

Usually a highly polar functional group is masked by conversion to ester, amide etc, akin to protecting group strategies in reorganising synthesis.

In metabolism, the carrier is cleaved off enzymatically

Question 5

What are the criteria of carriers for carrier pro drugs?

Answer 5

Cleaved rapidly

Form metabolites which are non toxic

Question 6

What is the difference between a bipartate and a tripartate prodrug?

Answer 6

Bipartate: drug is directly linked to a carrier e.g. Tolmetin, an NSAID
Tripartate: drug is linked to carrier via a linking structure e.g. Penicillin antibiotic

Question 7

What is the purpose of the linker in tripartate pro drugs?

Answer 7

The carrier may not cleave if linked directly to the drug, however it can be removed if it is separated by a linker.

Ideally the linker is readily removed or spontaneously collapses

E.g. Ampicillin is an antibacterial poorly absorbed through gut wall. We can mask the polar group to form a pro drug, however the OMe is not hydrolysed well due to steric hindrance from the penicillin skeleton, by adding a linker we form a good ampicillin pro drug, called bacampicillin

Question 8

How is the bacampicillin pro drug metabolised?

Answer 8

The extended ester is readily hydrolysed to give an unstable intermediate which collapses with a loss of ethanal to give the active drug,

Note that ethanol, ethanl and CO2 are natural metabolites, so there is no toxic response

Question 9

What are bioprecursor prodrugs?

Answer 9

These produce the active drug on metabolism

E.g. Prontosil which is metabolised to give sulfanilamide
Discovered in 1935, to have good in vivo anti bacterial properties but no activity in vitro. Later discovered metabolism by gut flora occured to give active sulfonamide

Question 10

What is prontosil rubrum?

Answer 10

Red dye used for colouring wool

Question 11

How can pro drugs be used to improve membrane permeability?

Answer 11

Some moieties such as carboxylic acids are important for binding but will hinder a drug crossing from cell membranes.
We dam mask the acid by converting it into an ester

Question 12

Why does converting a carboxylic acid into an ester improve its membrane permeability?

Answer 12

Ester is less polar than a carboxylic acid
It is better able to cross lipid membranes.
It is readily hydrolysed by enzymes in the bloodstream.
E.g. Enaoaprilate is an antihypertensive, but better absorbed as the prodrug enalapril which has a ester in place of a carboxylic acid

Question 13

Why is dipivaloyladrenaline better suited to treat glaucoma?

Answer 13

Adrenaline is poorly absorbed through the cornea.
Dipivaloyladrenaline is absorbed and hydrolysed by enzymes in the cornea, due to having an ester and propyl moiety in place of the 2 OH moieties

Question 14

What is a good way to get an amine across a lipid membrane?

Answer 14

Having it undergo N-alkylation
I.e. Adding a new methyl group makes it more lipophilic.
E.g. Barbituates which need to cross the bbb to be hypnotic

Question 15

What are the two ways amines can be made more lipid permeable?

Answer 15

By alkylating them

By conversion into an amino acid

Question 16

How does conversion of an amine into an amino acid improve its permeability?

Answer 16

Polar amino acids will complex to a carrier protein on the surface of cell membranes and are carried through the bilayer e.g. Dopamine for the treatment of Parkinson’s disease is too polar to cross the bbb but if it is converted to levodopa, it is an amino acid and can utilise carrier proteins as levodopa is very similar to phenylalanine

Question 17

How does levodopa utilise carrier proteins?

Answer 17

Its similarity to the amino acid phenylalanine essentially allows it to be recognised by the carrier protein and encapsulated
It is carried across the barrier and the acid group is removed by the decarboxylase enzyme i.e. Gets into amino acid backbone to get dopamine

Question 18

How can prodrugs be used to improve patient acceptance?

Answer 18

Some of the uncomfortable effects with taking drugs can be alleviated by modifying water solubility

E.g. Taste masking, slow release, minimising toxic effects

Question 19

How can prodrugs be used to mask the taste of bitter drugs?

Answer 19

Using long chain fatty acids as carriers gives prodrugs a bland taste.
The ester bond is hydrolysed after the drug is swallowed.
Therefore while in the mouth the taste of the drug does not reach the tastebuds e.g. Chloramphenicol an antibiotic with bitter taste, when added with palmitate, has a bland taste

Question 20

How do prodrugs achieve slow release?

Answer 20

Some drugs are eliminated from the body too quickly and other rugs may be required to treat a condition where a slow, prolonged activity is needed e.g. Patients with psychosis.

We would add a carrier that is broken down slowly e.g. Amide.
E.g. Tolmetin sodium, NSAID only had a half life of 1 hour, but after an amide was added, it prolonged its duration of action to 9 hiurs

Question 21

How can prodrugs be used to minimise toxic effects?

Answer 21

Some drugs are too toxic to be administered directly, so we use a prodrug that is unmasked in the bloodstream

Some side effects arise from high initial concentrations of the drug- we can use a carrier with a slow cleavage rate, achieving a slow release pro drug which avoids the side effects

Side effects arise from the presence of certain functionality, we can mask the with a remove able carrier.

E.g. Salicylic acid causes gastric irritation this is reduced by acetylation. Aspirin is a pro drug for salicylic acid and is hydrolysed by esterases AFTER gut absorption

Question 22

How does drug distribution lead to side effects?

Answer 22

A vast majority of drugs need to be transported throughout the body after absorption or injection which means that a much higher concentration needs to be administered which can cause side effects.
The drug may also interact with other targets –> toxicity

Question 23

How can prodrugs be site specific ?

Answer 23

We can design pro drugs which are onlt activated at the target site either by

Transport to the site of action
Cleaved only at the site of action
Unable to perfume from the target site rapidly

Question 24

What is the challenge with site specific prodrugs?

Answer 24

It is difficult to obtain prodrugs which satisfy all three requirements

Question 25

How do site specific pro drugs cleaved only at the target active site work?

Answer 25

They rely on some enzymes and transport systems found mainly at certain sites.
The site specific prodrugs are usually designed to be cleaved or modified by such enzymes

Question 26

What are examples of sites which may contain specific enzymes?

Answer 26

Tumour cells contain high proportions of phosphatases and peptidases

Virally infected cells contain specific viral enzymes, especially those involved in nucleic acid synthesis and kinases involved in phosphorylations

Blood brain barrier allows the passage of lipophilic molecules and has active transport systems for amino acids

Most other tissue types also possess higher levels of certain enzymes such as specific peptidases and esterases that can be taken advantage of

Question 27

What are examples of site specific prodrugs?

Answer 27

Cyclophosphamide which is a nontoxic precursor prodrug.
It is activated by phosphoramidases which are more abundant in tuner cells.
The active phosphoramide mustard is an alkylating agent and inhibits DNA synthesis

Question 28

What is the downside to cyclophosphamide?

Answer 28

The cleavage by phosphoramidases also occurs in the liver. This forms acrolein as a byproduct which can lead to serious side effects

Question 29

What is an example of an antiviral prodrug?

Answer 29

Some important antiviral drugs are target specific and interact best with virus specific enzymes e.g. Acyclovir = non toxic pro drug which is only toxic towards virally infected cells.

It is only phosphorylated by viral specific kinases so the active triphosphate is formed in high concentrations only in infected cells.
Triphosphate has a 100x greater affinity for viral DNA polymerase than human DNA polymerase

Question 30

How can prodrugs be targeted to the brain?

Answer 30

Carrier groups can be designed to take advantage of the hydrophobic nature of the blood brain barrier and amino acid transport systems present.

Hypophilic drugs can have a lipophilic carrier attached. The prodrug crosses the blood brain barrier and is cleaved.
The hydrophilic drug cannot recross and is trapped at the target site
E.g. Antibiotics targeted to the brain.
Dihydropyridines often used as a carrier group

Question 31

What are the problems of using pro drugs?

Answer 31

Prodrugs are more complex than normal drugs, -> production costs are higher

Cleavage occurs in biological systems so all compounds must be evaluated in vivo

There is considerable inter species variation. Prodrugs active in rats may not be active in uh imams

Difficult to obtain a prodrug that satisfies all criteria of a prodrug whilst retaining good pharmacokinetic properties

While the use of site specific prodrugs is very exciting, clinical use has been limited, especially in the treatment of tumours