1. Prodrug Approaches Course: Drug Design Course code: 0510412
Dr. Bilal Al-Jaidi
Dr. Balakumar Chandrasekaran
Assistant Professors,
Faculty of Pharmacy,
Philadelphia University-Jordan

2. Learning Outcomes At the end of this lesson students will be able to
Define and describe various applications of the 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.

3. Prodrug approach
Prodrug: is a pharmacologically inactive compound that is converted into an active drug by metabolic transformations.
Soft drug (antedrug): is pharmacologically active drug that will be metabolized to terminate its action and facilitate excretion.

4. The useful applications behind prodrug design
Improving aqueous solubility
Improving absorption and distribution
Site specificity: depends on the presence of certain enzyme that will release the active form of drug at the site of action
Increase biological stability: mainly by interfering with drug metabolism

5. The useful applications behind prodrug design
5. Minimize possible toxicity:
Unpleasant taste or odor
Gastric irritation
Pain at the site of injection
6. Improving patient compliance
7. Solve some formulation problems

6. Types of prodrugs
Carrier-linked: here the drug is linked to a carrier group that can be removed enzymatically:
Bipartate: if the drug is directly attached to the carrier group
Tripartate: if there is a linker group between the drug and the carrier moiety
Mutual prodrug: here two drugs are linked together, they are synergistic to each other

7. Types of prodrugs Bioprecursor:
Compound that is metabolized by molecular modification into either an active form or into an intermediate that will be farther metabolized.
Here oxidation is the main metabolic biotransformation involved in the activation of bioprecursors.

8. Types of prodrugs
Carrier-linked:
Bioprecursor:

9. The common carrier group is the ester (WHY?)
Availability of esterase enzyme
Possible of either increasing or decreasing the lipophilicity of the parent drug.
Can be either easily hydrolyzed or relatively stable ester

10. Carrier-linked prodrugs
Drugs with alcohol and carboxylic acid groups:
The common carrier group is the ester (WHY?)
Availability of esterase enzyme
Possible of either increasing or decreasing the lipophilicity of the parent drug.
Can be either easily hydrolyzed or relatively stable ester

11. Drugs with alcohol and carboxylic acid groups

12. Drugs with alcohol and carboxylic acid groups
Small sized esters will be easily hydrolyzed than sterically hindered esters
Electronic factor may play a role in the rate of hydrolysis:

13. Drugs with alcohol and carboxylic acid groups

14. Drugs with alcohol and carboxylic acid groups
Drugs having carboxylic acid group can be esterified to:
Increase lipophilicity.
Increase Pka: this can be done by making the choline ester of these drugs:

15. Drugs having 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.
Some are more susceptible to cleavage:
Amides of amino acids.
Phenyl carbamate

16. Drugs having amine moiety
amine prodrugs might have lowered pKa…lower ionization… more lipophilic than the parent drug, the followings are examples of some lipophilic prodrugs from amine:

17. Drugs having amine moiety

18. Drugs having amine moiety

19. Drugs having carbonyl group

20. Examples Prodrugs to increase water solubility:
Esters with anionic solubilizing agent are poorly hydrolyzed while with cationic solubilizing groups will be easily hydrolyzed.

21. Examples
Prodrugs to increase water solubility:

22. Examples
Prodrugs to improve absorption through biological membranes:

23. Examples
Prodrugs to improve absorption through biological membranes:

24. Examples Prodrugs for site specificity:
Increasing lipophilicity will increase the access to almost all tissues.
Factors affecting the penetration though BBB:
Molecular size.
Lipophilicity
Stability toward enzymes available in BBB

25. Examples Prodrugs for site specificity:
Progabide is an example.. Will b e hydrolyzed after passing the BBB.
Tumor cells have elevated amount of phosphatase and amidase.

26. Examples Prodrugs for site specificity:
Approaches of site specific anti-tumor agents:
Enzyme-prodrug therapy:
Achieve selective activation of prodrug at a desired site
Prodrug activating enzyme is incorporated into the target tumor cells, then the prodrug will be administered systemically (what are the drawbacks of this approach?)
Antibody-directed enzyme prodrug therapy:
An antibody produced against a tumor cell line.
Then linked to the exogenous activating enzyme.
This antibody-enzyme complex will be accumulated on the tumor cells.
Prodrug will be administered then will be activated once reaches tumor cells.

27. Examples Prodrugs for site specificity:
Antibody-directed enzyme prodrug therapy (ADEPT):

28. Examples Prodrugs for stability:
Either physicochemical stability or biological stability:

29. Examples
Prodrugs for stability:

30. Examples
Prodrugs to decrease ionization in GIT…. Gives better oral availability:

31. Examples Prodrugs to improve chemical stability:
Examples are the acid stable penicillins

32. Examples Prodrugs to improve rectal absorption:
Mainly drugs are absorbed from rectum through passive diffusion (the same as from intestine)
Passive diffusion depends on the degree of lipophilicity and water solubility.
Little amount of fluid is present in the rectum, this means that drug must have greater water solubility in order to be dissolved in rectum.

34. Examples Prodrugs to improve ocular delivery:
Problems in ocular delivery:
Is to attain the optimal drug concentration
Tear turn-over
Poor conjunctival absorption due to the specialized corneal membrane
Only 1-10% of the topically applied treatment to eye will be absorbed
LogP of drug administered to eye must be 2-3

35. Prodrugs to minimize toxicity:
Dipifevrin is an example…less toxic than epinephrine because it will act locally in the ocular cavity.
Aspirin prodrugs:

36. Prodrugs to encourage patient acceptance:

37. Prodrugs to eliminate formulation problems:
Example: formaldehyde is normally used as antiseptic and disinfectant, but it is highly unstable and toxic…converted to more stable Methenamine (Hexamine):

38. Macromolecular drug delivery
Drug here is covalently attached to a macromolecule such as synthetic polymers, glycoproteins, lipoproteins, albumin, liposome, DNA and antibodies.
Advantages:
Targeting specific target.
Improving therapeutic index and lowering toxicity
Reducing drug metabolism and excretion

39. Macromolecular drug delivery
Disadvantages:
Steric hindrance may affect chemical and enzymatic hydrolysis of drug-macromolecule complex.
Immunogenic
Large –sized complex…might not get into the cell, except by pinocytosis…then drug will be released after biodegradation by lysosomes.

40. Macromolecular drug delivery
By synthetic polymers:
Drug here is attached to totally synthetic polymers
Sustained release of ibuprofen
Prolonged anti-inflammatory effect

41. Macromolecular drug delivery
By synthetic polymers:
Sometimes a spacer is added between the drug and the macromolecule…to enhance the biodegradation and the release of drug:

42. Macromolecular drug delivery
By poly amino acids:
Here the drug is attached to peptide chain.
The advantage is the biodegradability of the peptide chain…mainly when the amino acids are in the L-stereochemistry.

43. Macromolecular drug delivery
To improve site specificity:
Solubilizer group such as ionizable hydrophilic group
Homing device….for targeting specific site…such as antibodies

44. Macromolecular drug delivery
To improve site specificity:
40X less toxic than
nitrogen mustard

45. Tripartate prodrugs
This is used to overcome the problem of too labile or too stable bipartate prodrugs
Sometimes called double prodrugs.
Here the drug is attached to a linker that is in turn will attach to the carrier group.
First the carrier will be removed by hydrolysis, then an unstable intermediate will be formed…rearranged to release the active drug

46. Tripartate prodrugs
The methyl ester did not give the same improvement in absorption and activity (why?).

47. Dihydropyridine as a carrier for CNS targeting

48. Dihydropyridine as a carrier for CNS targeting
In this delivery system:
The dyhydropyridine-drug complex will be lipophilic…better penetrate into the CNS through BBB.
Then the dihydropyridine will be enzymatically oxidized to give the pyridinium ion…ionized…water soluble… trapped within the CNS.
Then the drug-pyridinium complex will be hydrolyzed to release the active drug and the non toxic N-methyl nicotinic acid.

49. Redox tribartate drug delivery system

50. Peptides as drug delivery system
Peptides are normally coupled to drugs to:
Improve oral availability
Improve skin penetration
Enhance antibacterial action.
This depends on the fact that cell membranes have peptide transport integral proteins called permease that will actively ingest peptides and peptidomimetic agents into the mammalian cells as well as bacterial cells.

51. Examples of peptide carrier systems

52. 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.

53. Mutual prodrugs
If the two synergistic drugs are given at the same time but separately, they will not necessarily reach the same site of action at the same time.
Example: the common combination of amoxicillin and clavulanic acid, or Gentamicin with Carbenicillin.
Example of mutual drug is Sultamicillin

55. Bioprecursor prodrugs
Bioprecursor prodrugs mostly use either oxidative or reductive activation reactions.
The main activation pathways are:
Proton activation.
Hydrolytic activation
Elimination activation
Oxidative activation
Reductive activation
Nucleotide activation
Phosphorylation activation
Sulfation activation
Decarboxylation activation

56. Bioprecursor by elimination activation
Isoxazole ring is known to undergo elimination to nitrile

57. Bioprecursor by N and O dealkylation

58. Bioprecursor by Oxidative deamination

59. Bioprecursor by aromatic hydroxylation

60. Bioprecursor by Alkene oxidation

61. Bioprecursor by Reduction

62. Bioprecursor by Nucleotide activation

63. Bioprecursor by Phosphorylation

64. Bioprecursor by decarboxylation

65. Bioprecursor by Decarboxylation
In order to increase the concentration of L-dopa reaching brain, Peripheral L-amino acid decarboxylase inhibitor is normally administered with L-dopa; carbidopa or benserazid are normally given.

66. Recommended Books
The organic chemistry of drug design by Richard B. Silverman. Second edition, Elsevier, 2004.
An introduction to Medicinal Chemistry by Graham L. Patrick. Fourth edition, Oxford, 2009.