Course: Drug Design Course code: 0510412 design...groups I. Drugs with alcohol and carboxylic acid groups:-Ester group is the common carrier group. Reasons:- Availability of esterase

Course: Drug Design Course code: 0510412

Dr. Soha Telfa

and

Dr. Balakumar Chandrasekaran

Assistant Professors,

Faculty of Pharmacy,Philadelphia University-Jordan

Learning OutcomesAt the end of this lesson students will be able to

Define and describe various applications of prodrugs.

Explain different types of prodrugs.

Describe the carrier-linked prodrugs with examples.

Define and explain macromolecular drug delivery.

Describe the importance of mutual prodrugs.

Explain bioprecursors with suitable examples.

Prodrug Prodrug is a pharmacologically inactive compound

that is converted into an active drug by metabolic transformations.

A prodrug can also be activated by a non-enzymatic process such as hydrolysis.

Prodrug Design is a lead modification approach that is used to correct some defects in a drug candidate.

Soft drug (antedrug): is pharmacologically active drug and uses metabolism as a means of promoting excretion.

Utility or the useful applications of Prodrugs1. Improving aqueous solubility.

2. Improving absorption and distribution.

3. Improving the site-specific delivery.

4. Increasing the stability.

5. To achieve the prolonged release of drug.

6. To minimize the toxicity.

7. To solve formulation problems

8. Improving patient compliance and to overcome: Unpleasant taste or odor,

Gastric irritation,

Pain at the site of injection.

Types of prodrugs

Carrier-linked:

Bioprecursor:

Types of prodrugsI. Carrier-linked Prodrug

It is a compound that contains an active drug linked to a carrier group that can be removed enzymatically.

Example: Ester in prodrug can be hydrolyzed to an active

carboxylic acid containing drug.

They are subdivided into:-

Bipartate: Prodrug having one carrier attached to the drug directly.

Tripartate: carrier moiety connected to a linker group that is connected to the drug

Mutual prodrug: It consists of two synergistic drugs linked together (one drug is a carrier for the other).

II. Bioprecursor Prodrug

It is a compound that is metabolized by molecular modification into a new active form or which can be metabolized further to the active drug.

Here oxidation is the main metabolic biotransformation involved in the activation of bioprecursors.

R-NH2 R-CHO R-COOH

Types of prodrugs

Metabolic oxidation Metabolic oxidation

Bioprecursor Active Drug

I. Carrier-linked prodrugs

Ideal drug carrier must:

1. Protect the drug until it is at the site of action.

2. Localize the drug at the site of action.

3. Allow for the drug release by chemically or enzymatically.

4. Minimize host toxicity.

5. Biodegradable, inert and non-immunogenic.

6. Be easily prepared inexpensively.

7. Stable in its dosage form.

Carrier-linkages for various functional groups

I. Drugs with alcohol and carboxylic acid groups:-

Ester group is the common carrier group.

Reasons:-

Availability of esterase enzyme.

Possible of increasing or decreasing the lipophilicity of the parent drug.

A variety of stabilities of ester can be obtained by manipulation of electronic and steric factors.

Alcohol containing drugs can be acylated using(i) Carboxylic acid (to decrease water solubility).(ii) Carboxylic acid containing amino group (amino acid) or

additional carboxylic acid (to increase water solubility).

In some cases, esters are not good substrates and hydrolyzed by (i) Endogenous esterases (or) Sulfatases (or) Phosphatases

So different esters can be used to accelerate the rate of hydrolysis. Example: Succinate ester by intramolecular catalysis.

Carboxylic acid containing drugs can be esterified using alcohol.

pKa of carboxylic acid can be increased by conversion to:

(i) Choline ester(ii) Amino ester(iii) 3-phthalidyl ester

II. Drugs with amine moiety:-

N-acylation of amine moiety to amide is NOT commonly used.

Reasons:-

Amides are stable towards metabolic hydrolysis.

Amides are less basic.

Amides of amino acids are more susceptible to enzymatic cleavage.

Example:-Phenyl carbamate (rapidly cleaved by plasma enzymes)

Approach to decrease pKa of amine moiety to increase the lipophilicity is the conversion to imine moiety.

Example:- Progabide

Most of solid tumours are hypoxic(low oxygen), reductive activation mechanism is also important. Example:- Reduction of nitro aromatic prodrugs.

III. Drugs with carbonyl (C=O) moiety:-

The prodrug forms of carbonyl (C=O) groups of aldehydes and ketones are:-

Examples of Carrier-linked BipartateProdrugsI. Prodrugs for increased water solubility

Poorly water soluble Corticosteroidal drugs are Predinisolone and Methylpredinisolone

Factors to be considered:-

(i) The ester must be stable enough in aqueous solution

(long half-life).

(ii) The ester must be hydrolysed in vivo so that it can release

the drug (short half-life).

So, solubilizing group must be selected carefully to obtain optimal conditions.

Esters with anionic solubilizing agent are poorly hydrolyzed while with cationic solubilizing groups will be easily hydrolyzed.

Example-1: Predinisolone Drug

Example-2: Benzocaine Drug

Benzocaine is a local anesthetic drug (more lipophilic) andconverted to water soluble amide prodrug.Amidase enzyme in human serum hydrolyze this amide.

II. Prodrugs for improved Absorption and

Distribution

Example-1: Flucinolone Drug

Steroids having low skinabsorption due to hydroxyl groups (-OH) which interact with skin/binding-site of keratin. Corticosteroids like Flucinolonecan be used for skin allergy and inflammation. They have lower skin permeability. So to increase the skin permeability, the prodrugFlucinolone acetonide was formulated.

Example-2: Epinephrine Drug

Epinephrine is an antiglaucoma drug (poor corneal membrane penetration in eyes) and converted prodrug Dipivefrin (better corneal penetration) which can be hydrolyzed by the enzyme esterases.

Factors affecting the delivery of drugs to Brain through Blood-Brain Barrier (BBB):

BBB is lipid-like protective barrier that prevents the entry of hydrophilic drugs to brain

BBB has active enzyme systems that protect the brain.

III. Prodrugs for Site-specificity

So, for better penetration though BBB, the drugs must have adequate Molecular size and Lipophilicity.

Example-1: GABA Drug

GABA is polar, anticonvulsant drug which cannot penetrate BBB. So, Progabide a prodrug of GABA is used which can penetrate BBB due to high lipolphilicity.

Tumor cells have elevated amount of phosphatase and amidase.

Diethylstilbestrol diphosphate prodrug was designed for the site-specific delivery of Diethylstilbestrol to prostatic carcinoma tissue.

Example-2: Diethylstibestrol Drug

Sometimes Prodrugs are too polar, low enzymatic selectivity, and have low tumour cell perfusion rate.

To overcome these drawbacks and to achieve selective activation at the desired site (tumour cells), Enzyme-prodrug therapy (EPT) was developed.

In this approach, Prodrug activating enzyme is incorporated into the target tumor cells, then the non-toxic prodrug will be administered systemically to the tumours.

The prodrug is selectively converted into the active cancer

drug in a high local concentration inside the tumour cell.

Antibody-directed enzyme prodrug therapy (ADEPT) is a type of EPT.

Enzyme Prodrug Therapy (EPT)

In this approach, an antibody produced against a tumor cell line and linked (attached) to the exogenous enzyme.

This antibody-enzyme conjugate is administered and has accumulated on the tumor cells.

The excess unbound to the tumour cell is given sufficient time for their clearance from the blood.

Then, the prodrug will be administered then activated once reaches tumor cells by the enzyme conjugated within the antibody.

The advantage of ADEPT is increased selectivity for the release of high concentrations of the drug at the targeted cells.

Antibody-directed Enzyme Prodrug Therapy (ADEPT)

Example: Nitrogen mustard activation by the enzymeCarboxypeptidase G2.

Humanized monoclonal antibody conjugated to the bacterialenzyme carboxypeptidase G2 for the delivery of nitrogen mustard as a conjugate with glutamate.

IV. Prodrugs for Stability

Example-1: Propranolol (Antihypertensive Drug)

Due to first-pass effect, propranolol has low oral bioavailability.O-glucuronide of propranolol is the major metabolite. The hemisuccinate ester of propranolol (prodrug) is

metabolically stable, can be administered orally and blocks the glucuronide formation.

Example-2: Naltrexone (treatment of opioid addiction)

V. Prodrugs to minimize toxicity

Example: Aspirin (NSAID)

Side effects of Aspirin: Gastric irritation and ulcerogenicity. Reason: Accumulation of the acid in gastric mucosal cells. Solution: Esterification of Aspirin.

VI. Prodrugs to encourage patient acceptance

Example-1: Sulfisoxazole (Antibacterial Sulfa Drug)

Example-2: Clindamycin (Antibiotic Drug)

Clindamycin generates pain on injection and bitter taste orally.

Prodrug Clindamycin Phosphate generates no pain.

Prodrug Clindamycin Palmitate gives no bitter taste.

VII. Prodrugs to eliminate formulation problems

Example: Formaldehyde (Urinary antiseptic, Disinfectant)

Highly concentrated Formaldehyde solution is toxic. Reaction of formaldehyde with ammonia produces a stable

Methenamine (prodrug). pH of urine inside the urinary bladder is acidic, so

methenamine hydrolyzed to release formaldehyde. To prevent the hydrolysis of the prodrug methenamine in

the acidic environment of stomach, the enteric coated tablets are formulated.

Macromolecular drug delivery Another carrier-linked bipartate prodrug approach is

Macromolecular Drug Delivery.

The drug is covalently attached to a macromolecule such as synthetic polymers, glycoproteins, lectin, lipoproteins, DNA, albumin, liposome, hormone and antibodies.

Advantages:- Targeting specific site.

Improving therapeutic index and lowering toxicity.

Reducing premature drug metabolism and excretion.

Disadvantages:-

Steric hindrance may affect chemical and enzymatic hydrolysis of drug-macromolecule complex.

May be Immunogenic.

Large –sized complex…might not get into the cell, except by pinocytosis…then drug will be released after biodegradation by lysosomes.

May not be well absorbed through oral route. So

alternative route may be used.

Macromolecular drug delivery

Drug is attached to totally synthetic polymers

Advantages of Ibuprofen polyoxyethylene diester:-

Sustained release of ibuprofen

Prolonged anti-inflammatory effect

High plasma half-life

Macromolecular drug deliveryExample-1: Synthetic Polymer

Sometimes a spacer is added between the drug and the macromolecule…to enhance the biodegradation and the release of drug and avoids steric hindrance of polymer.

Macromolecular drug delivery

Here the drug is attached to peptide chain.

The advantage is the biodegradability of the peptide chain than the synthetic polymers.

Macromolecular drug deliveryExample-2: Poly (α-amino acids)

Macromolecular drug deliveryExample-3: To improve site specificity

Solubilizer group such as ionizable hydrophilic group can be added.

Homing device….for targeting specific site…such as antibodies.

Components of the Nitrogen mustard macromolecule are:- Poly (L-glutamate) is used as

backbone. Unsubstituted glutamate side

chain carboxylate groups are water solubilizing groups.

Glutamate side chain is the spacer.

Immunoglobulin is the homing device.

Macromolecular drug delivery

Advantages• Less toxic than nitrogen mustard.• 40 Times better therapeutic index.

This is used to overcome the problem of too labile ortoo stable bipartate prodrug linkages (ester; sterichindrance)

Here the drug is attached to a linker that is furtherattached to the carrier group.

First the carrier will be removed by enzymatichydrolysis, then an unstable intermediate will beformed…spontaneously (self immolative) rearranged torelease the active drug.

One approach to design drug-linker is double prodrugor double ester concept.

Tripartate prodrugs

Tripartate prodrugs of Ampicillin

• Only 40% of ampicillin is absorbed through oral route.• So 2.5X times more dose needed for oral administration.• High dose: rapid resistance, GIT microbes get affected.• The methyl ester did not give the same improvement in

absorption and activity because Esterases in rodents and human are different. Steric hindrance also possible.

• So, double ester prodrugs were prepared.

Tripartate Double ester prodrug of Ampicillin

Hydrolysis of terminal ester of Bacampiciliin gave unstable hydroxymethyl ester that spontaneously decomposed to release ampicillin.

So, Bcampicillin is a prodrug, non-toxic, 99% absorption and release active drug Ampicillin within 15 minutes.

So less dose is sufficient.

Dihydropyridine as a carrier for CNS targeting (Bipartate)Reversible redox drug delivery system The lipophilic carrier

Dihydropyridineis attached to hydrophilicdrug. The nitrogen in the Dihydropyridine is conjugated into carbonyl thereby it is less reactive to nucleophiles, more stable

for hydrolysis.

Inside the brain, the carrier is converted into hydrophilicspecies. So, no conjugation to carbonyl and pyridiniumion now activates the carbonyl group for nucleophilic attack.

N-methyl nicotinic acid.Non-toxic and actively transported out from brain.

Oxidation of dihydro-pyridine to pyridiniumion prevents the drug from escaping out fromthe brain because it becomes charged.

It can have better watersolubility.

Then the drug-pyridinium complex will be hydrolyzed to release the active drug and the non toxic N-methyl nicotinic acid.

Dihydropyridine as a carrier for CNS targeting (Tripartate)

Example-1: β lactam antibiotics for the treatment of bacterial meningitis

β lactam antibiotics are hydrophilic, can reach brain very slowly.

They are actively transported out from the brain. Also, cerebrospinal fluid (CSF) contains less than 0.1% of

the immunocompetent leuckocytes when compared to the blood.

It has no immunoglobulins. So antibody generation is not significant against the bacterial strains.

Thus, β lactam antibiotics are not effective in the treatment of brain infections.

Therefore, β lactam antibiotics are converted into their tripartite prodrugs for the delivery in high concentrations in the brain.

• Due to low lipophilicity, 5-fluorouracil has low bioavailability. So peptidyl derivative of 5-fluorouracil was prepared that showed 5 times better skin penetration and rapid metabolism.

• Microbes have specialized transport system for the uptake of peptides (permeases) and these have side-chain specificity. L, L stereochemistry on peptidyl prodrug was active.

Example-2: 5-fluorouracil for treatment of skin infections

Mutual prodrugs Applied when it is necessary for two synergistic drugs to be

at the same time at the same site.

Mutual prodrug is a bipartate or tripartate prodrug in which the carrier is the synergistic drug with the drug to which it is linked.

Examples of Bipartate mutual prodrugs:-

Combination of amoxicillin and potassium clavulanate

Combination of pivampicillin and penicillanic acid sulfone

Tripartate mutual drug is Sultamicillin

Bioprecursor prodrugs History: Prontosil (azo prodrug, active in vivo) reduced to

sulphanilamide (amine sulfa drug).

Bioprecursor prodrugs mostly use either oxidative or reductive activation reactions.

But carrier-linked prodrugs depends on hydrolysis reactions.

The main activation pathways are:

Proton activation Phosphorylation activation

Hydrolytic activation Sulfation activation

Elimination activation Decarboxylation activation

Oxidative activation

Reductive activation

Nucleotide activation

Bioprecursor by Elimination activation

Leflunomide inhibits the pyrimidine biosynthesis by blocking

enzyme Dihydroorate dehydrogenase, but less potent.

Isoxazole ring undergoes elimination to nitrile.

This nitrile metabolite is highly potent inhibitor than parent

drug Leflunomide.

Bioprecursor by O-dealkylation

Bioprecursor by Oxidative deamination

Phosphoramidases are present in cancer cells at higher levels.

Cyclophosphamide is a prodrug that requires activation by Oxidative Deamination mechanism.

Bioprecursor by Aromatic hydroxylation

Bioprecursor by Alkene oxidation

Bioprecursor by Reduction

Bioprecursor by Nucleotide activation

Bioprecursor by Phopshorylation

Acyclovir (antiviral prodrug, highly effective against herpes simplex virus and varicella zoster.-phosphorylated to monophosphate by viral thymidine kinase.

-conversion of mono phosphate to diphosphate by guanylate kinase.-conversion of di phosphate to triphosphate by phosphoglycerate kinase.-This acyclovir triphosphate was selectively uptaken by viral DNA-polymerase due to thestructural similarity with 2’-deoxyguanosine triphosphate.

This affects the viral replication and virus will die.

Bioprecursor by Decarboxylation

Parkinson’s disease is due to the deficiency of dopamine. Exogenous dopamine cannot cross BBB. So, Levodopa can be given and transported into the

brain where it is decarboxylated by the enzyme dopadecarboxylase (Aromatic L-amino acid decarboxylase).

This enzyme also present outside the CNS.More than 95% of the administered Levodopa

undergoes first-pass metabolism by liver. Possibly 1% of levodopa only reaching the CNS making

less effective. In order to prevent this, Peripheral dopa decarboxylase

(Aromatic L-amino acid decarboxylase) must be inhibited.

So, levodopa can reach CNS safely at higher concentration.

Peripheral dopa decarboxylase (Aromatic L-amino acid decarboxylase) inhibitor such as Carbidopa can be combined with levodopa for better treatment.

Carbidopa is a charged molecule, cannot cross BBB and used in United States.

Another Peripheral dopa decarboxylase (Aromatic L-amino acid decarboxylase) inhibitor Benserazide is used in Europe and Canada.

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1. The organic chemistry of drug design by Richard B. Silverman. Secondedition, Elsevier, 2004.

2. An introduction to Medicinal Chemistry by Graham L. Patrick. Fourthedition, Oxford, 2009.

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