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

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

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”

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)

Azo Compounds Sulfazalazine Used in the management of Ulcerative Colitis

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

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

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

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?)

OXIDATIVE ACTIVATION THE CASE OF NABUMETONE

Oxidation of Nabumetone NSAID General Structure

Oxidation of Nabumetone

THE CASE OF REDUCTIVE ACTIVATION

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

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

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

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.

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.

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

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

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