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Targeted prodrug design for drug delivery
- 1. TARGETED PRODRUG DESIGN FOR DRUG DELIVERY Thomas Filarowski - Chemistry
- 2. Introduction ■ Almost all drugs possess some undesirable physiochemical and biological properties. ■ Drug candidates are often discontinued due to issues of poor pharmacokinetic properties or high toxicities. ■ Their therapeutic efficacy can be improved by eliminating the undesirable properties while retaining the desirable ones. ■ This can be achieved through biological, physical or chemical means.
- 3. What is a prodrug? A substance which is administered in its inactive form but is metabolised in the body to release the active parent drug. This is to elicit its pharmacological response within the body at the desired site of action.
- 4. History of prodrugs ■ The first compound fulfilling the classical criteria of a prodrug was acetanilide (Cahn and Hepp, 1867).Which is hydroxylated to biologically active acetaminophen. ■ Another historical prodrug is Aspirin (acetylsalicylic acid), synthesised in 1897 by Felix Hoffman (Bayer, Germany) and introduced into medicine by Dreser in 1899. ■ The concept of a prodrug was intentionally used for the first time by Parke-Davis company for the modification of chloramphenicol structure to improve the antibiotic’s bitter taste and poor solubility in water.
- 5. Objectives of prodrug design ■ Pharmaceutical – Improve solubility, chemical stability, decrease irritation and/or pain. ■ Pharmacokinetic – Improve absorption, decrease presystemic metabolism, increase organ/tissue-selective delivery of the active agent. ■ Pharmacodynamic – Decrease toxicity and improve therapeutic index.
- 6. FDA approved prodrugs 2015 Drug Name Prodrug Approval Date Approved Use Cresemba Isavuconazonium sulfate 06/03/2015 Invasive aspergillosis and invasive mucormysis Entresto Sacubitril 07/07/2015 Heart Failure Xuriden Uridine triacetate 04/09/2015 Hereditary orotic aciduria Aristada Apipirozole lauroxil 06/10/2015 Schizophrenia Genoya Tenofovir alafenamide 05/11/2015 HIV-1 infection Ninlaro Ixazomib 20/11/2015 Multiple myeloma Uptravi Selexipag 22/12/2015 Pulmonary arterial hypertension Approximately 10% of all drugs world wide can be classified as prodrugs
- 7. Prodrug Classification ■ Carrier linked prodrugs ■ Bio-precursor prodrugs ■ Polymeric prodrugs Macromolecular prodrug which is dispersed or incorporated into the polymer.
- 8. Site specific drug delivery in chemotherapy ■ Many chemotherapy drugs for cancer lack tumour specificity. ■ Directed Enzyme ProdrugTherapy ■ ADEPT ■ GDEPT ■ VDEPT ■ PDEPT ■ DEPT strategies are an experimental method of reducing the systematic toxicity of a drug by achieving high levels of the active drug only at the desired site.
- 9. Why I chose this literature review? ■ Interest in the subject area. ■ Expanding my knowledge base outside of pure chemistry. ■ Improving my career possibilities. ■ Wide range of classical and modern literature.
- 10. How does it relate to my course? ■ Pharmacology – Targeted drug design ■ Medicinal Chemistry and Drug Discovery – Drug discovery process ■ Advanced Organic Synthesis and Spectroscopy – Synthesis and analysis of drugs
- 11. Future Career