1. Medicinal Chemistry Lecture Prodrugs of Functional Groups & Bio precursor Drugs Chemical Delivery Systems
Joseph O. Oweta | PHS 2201

2. Objectives Azo Linkages Carbonyl Compounds Bio precurosor Drugs
Prodrugs for site specific Delivery

3. Azo Compounds
Amines may be incorporated into azo compounds to give pro drugs.
IUPAC defines azo compounds as: "Derivatives of diazene (diimide), HN=NH, wherein both hydrogens are substituted by hydrocarbyl groups”

4. Azo Compounds
Azo compound prodrugs are metabolised by azo reductases that are produced by gut microflora.
The first azo compound prodrug was for prontosil (broken doen to sulfanilamide)

5. Azo Compounds Sulfazalazine
Used in the management of Ulcerative Colitis

7. Carbonyl Compounds
Sp2 of Carbonyl Cpds Hybridised carbons converted to Sp3
Upon Hydrolysis there’s reconversion to Carbonyl Functionalities
Antibacterial concentrated in Urine

8. Carbonyl Compounds
Methenemine is enteric coated to avoid hydrolysis in acidic environment of the Stomach.
Hydrolysis in acidic Urine (6.0 – 7.0)
Limited clinical application has been found for this functional group as well as oximes, imines etc

9. Bioprecurosr Drugs
Don't contain a carrier moiety but are functionally latent prior to chemical or metabolic transformation.
Activation could be:
Oxidation
Reductive activation
Phosphorylation
Chemical activation

10. Bioprecurosr Drugs Oxidation is the most common
Carried out by endogenous enzymes
Mainly the Cytochrome P-450 isozymes
Primarily act for Phase 1 Metabolism of xenobiotics
This is manipulated for bio precursors
Phosphorylation is mainly strategic for antivirals (why?)

11. OXIDATIVE ACTIVATION
THE CASE OF NABUMETONE

12. Oxidation of Nabumetone NSAID General Structure

13. Oxidation of Nabumetone

14. THE CASE OF
REDUCTIVE ACTIVATION

18. Chemical Activation
Read and make notes on the activation of PPI’s

19. Delivery Systems Generally
The goal of delivery systems is to protect the drug from the nonspecific environment and the non specific environment from the drug.
Site specific delivery has been specifically investigated for drugs with narrow therapeutic indices e.g. anticancer drugs

20. Delivery Systems Generally
Approaches include: [Some under consideration]
Prodrugs
Proteins
Polysacharides
Liposomes
Emuslions
Cellular carriers
Implants etc

21. Chemical Delivery Systems
An application of prodrugs to target a drug to its site of action.
Site specific delivery is based on higher levels of metabolism/chemical activity at the site of action.
Prodrugs are designed to act as substrates in the above pathway to give a high yield of active drugs at the site of action.

22. Chemical Delivery Systems
Factors affecting relative success of a site- specific delivery system include:
Extent of organ perfusion
Rate of conversion in both target and non target sites
Input/out put rates of prodrug and drug from the active site.

23. Prodrugs for Site Specific Delivery
Requires drug to be readily transported to the site of action.
Rapidly absorbed at the site
Selectively activated to active relative to activation at non drug sites
E.g activation at kidneys and liver is high due to good perfusion
Disdavantagous for other organs/tissues
Once activated  slow migration from the site

24. Prodrugs for Site Specific Delivery
Therefore using prodrugs for site specific targeting is complex…..examples (Read and Make notes)
Methamine for formaldehyde delivery to the urinary tract.
Activation of antiviral drugs (not phosphorylated by mammalian cells)
L-Dopa decarboxylated to dopamine
Lipophyillic drugs for CNS Delivery
Lipophillic esters of epinephrine to the eye
GIT delivery

25. Summary Prodrugs were probably in use before concept discovery
This framework is however, of imense importance in drug discovery and Design