PRODRUG DESIGN.pptx

The classical approach for prodrug design uses the non-specific strategy of covalently modifying the drug of interest by attaching hydrophilic functionalities

1. PRODRUG DESIGN SUBMITTED BY, Manimegalai.G M.Pharm -I year Advanced Medicinal Chemistry 8/20/2022 Department of Pharmaceutical Chemistry 1

2. INTRODUCTION A Prodrug is pharmacologically inactive compound that is converted into active drug by a metabolic biotransformation . Prodrug enhanced the usefulness of various therapeutic agents by altering the physicochemical properties, pharmacokinetics and biopharmaceutical properties. It might alter the tissue distribution , efficacy and toxicity of parent drug. 8/20/2022 Department of Pharmaceutical Chemistry 2

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4. REASONS FOR PRODRUG APPROACH Improved aqueous solubility Improved absorption and distribution Site specificity Improved stability of drugs For prolonged release To reduce toxicity In poor patient acceptability 8/20/2022 Department of Pharmaceutical Chemistry 4

5. BASIC CONCEPT Prodrugs are pharmacologically inactive derivatives of active drugs that are design to maximize the amount of active drug that reaches its site of action, through manipulation of physicochemical , biopharmaceutical and pharmacokinetic properties of drug. They are converted into active drug within the body through enzymatic or non-enzymatic reaction. Promoiety -Drug 8/20/2022 Department of Pharmaceutical Chemistry 5

6. CARRIER LINKED PRODRUGS It is a complex that comprises an active drug which is temporarily attached to some carrier with covalent linkage the carrier group can be detached enzymatically. After administration to the body, the prodrug undergoes biotransformation and converted to active compound . Bipartite prodrug Tripartite prodrug Mutual prodrug 8/20/2022 Department of Pharmaceutical Chemistry 6

7. BIPARTITE PRODRUG It is a prodrug composed of one carrier attached to the drug.( Drug+ Carrier) These are greatly modified lipophilicity due to the attached carrier . The active released by hydrolytic cleavage either chemically or enzymatically. For eg. , Tolmetin – glycine prodrug (NSAIDs) 8/20/2022 Department of Pharmaceutical Chemistry 7

8. TRIPARTITE PRODRUG In a tripartite prodrug, the carrier is not connected directly to the drug, but rather to a linker which is attached to the drug. This allows for different kinds of functional to be incorporated for varying stabilities and it also displaces the drug farther from the hydrolysis site, which decrease the steric interference by the carrier. The drug – linker connection however, must be designed so that it cleaves spontaneously after the carrier has been detached. 8/20/2022 Department of Pharmaceutical Chemistry 8

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10. MUTUAL PRODRUGS It consist of two pharmacologically active agents coupled together so that each act as a promoiety for the other agent. It is a bipartite or tripartite prodrug in which the carrier is a synergistic drug with the drug to which it is needed. For eg. , Benorilate (Mutual prodrug of aspirin and paracetamol) 8/20/2022 Department of Pharmaceutical Chemistry 10

11. BIOPRECURSORS PRODRUG Bioprecursors results from the molecular modifications of the compound. There is no need of promoiety in bioprecursors . Carrier linked podrugs rely largely hydrolysis reaction for their effectiveness, whereas Bioprecursors prodrugs mostly utilize their oxidative or reductive activation reaction . Reductive Bioactivation Oxidative activation Oxidative deamination N-oxidation Azo reductive activation Sulfoxide reduction 8/20/2022 Department of Pharmaceutical Chemistry 11

12. REDUCTIVE BIOACTIVATION Omeprazole , effectively inhibits gastric secretion by inhibiting the gastric H+ K+ ATPase. This enzyme is responsible for gastric acid secretion and located in the secretory membranes of parietal cells. Invivo Omeprazole is transformed into the active inhibitor, a cyclic sulfonamide, which forms disulfide bridge with thiol group of the enzyme and thus inactivates enzyme 8/20/2022 Department of Pharmaceutical Chemistry 12

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14. OXIDATIVE ACTIVATION Bioprecursor prodrug is activated by O-dealkylation is the analgesic and antipyretic agents Phenacetin , which is activity to its conversion by O-dealkylation metabolism to Acetaminophen. 8/20/2022 Department of Pharmaceutical Chemistry 14

15. OXIDATIVE DEAMINATION Cyclophosphamide is an alkylating agent it needs oxidative deamination for active metabolite . 8/20/2022 Department of Pharmaceutical Chemistry 15

16. N- OXIDATION Pralidoxime is an antidote for poisoning by organophosphorus compound which is believed to be activated by N- oxidation. 8/20/2022 Department of Pharmaceutical Chemistry 16

17. AZO REDUCTIVE ACTIVATION Sulfasalazine used in the treatment of inflammatory bowel disease is reductively cleaved by anaerobic bacteria in the lower bowel to 5- amino salicylic acid and sulfapyridine . 8/20/2022 Department of Pharmaceutical Chemistry 17

18. SULFOXIDE REDUCTION The antiarthritis drug sulindac is an indene isostere of the drug Indomethacin. Invivo it undergoes sulfoxide reduction to form an active metabolite sulindac sulfide. 8/20/2022 Department of Pharmaceutical Chemistry 18

19. PRODRUGS OF FUNCTIONAL GROUP CARBOXYLIC ACID AND ALCOHOL Prodrugs of carboxylic acid & alcohol functionalities can be prepared by conversion to esters. The esters can be easily hydrolysed by esterase enzymes present in plasma and other tissues to give active drug. 8/20/2022 Department of Pharmaceutical Chemistry 19

20. AMINES Due to the high stability and lack of amidase enzyme necessary for hydrolysis, the conversion of amines to amide as a prodrug is not been used for most of the drugs. 8/20/2022 Department of Pharmaceutical Chemistry 20

21. AZO LINKAGE Prodrugs of amines are occasionally prepared by incorporating them into an azo linkage. By the action of azo reductase the amino compounds are released. For eg. , 8/20/2022 Department of Pharmaceutical Chemistry 21

22. CARBONYL GROUP For eg. , Hexamine releases Formaldehyde in the Urine(acidic pH) which act as an antibacterial agent. 8/20/2022 Department of Pharmaceutical Chemistry 22

23. PRODRUGS TO IMPROVE PATIENT ACCEPTABILITY Painful injections and unpleasant taste or odour are the most common reasons for the lack of patient acceptance of a drug. For eg. , Ethyl Mercaptan is a foul smelling liquid used in the treatment of leprosy. This is converted to phthalate ester, a diethyl dithioisophthalate that has higher boiling point and is odourless . 8/20/2022 Department of Pharmaceutical Chemistry 23

24. PRODRUG FOR IMPROVED ABSORPTION AND DISTRIBUTION The skin is designed to maintain the body fluids and prevent absorption of xenobiotics into the general circulation. Consequently , drugs applied to the skin are poorly absorbed. Even steroids have low dermal permeability if they contain OH groups that can interact with the skin or binding site in the keratin. Corticosteroids for the topical treatment of inflammatory , allergic and pruritis skin conditions can be made more suitable for topical absorption by esterification. 8/20/2022 Department of Pharmaceutical Chemistry 24

25. Fluocinonide is a prodrug of Flucinolone acetonide used for inflammtory and pruritic manifestation . Once absorbed through the skin an esterase release the drug. Fluocinolone acetonide R =H (active) Fluocinonide R= COCH 3 ( prodrug ) 8/20/2022 Department of Pharmaceutical Chemistry 25

26. PRODRUG FOR SITE SPECIFICITY Blood Brain Barrier a unique lipid like protective barrier that prevents hydrophilic compounds from entering the brain unless they are actively transported. An increasing the brain concentration of the inhibitory neurotransmitter GABA results in anticonvulsant activity. However, GABA is too polar to cross the BBB so it is not an effective anticonvulsant drug. 8/20/2022 Department of Pharmaceutical Chemistry 26

27. Progabide is an effective lipophilic analog of GABA that crosses the BBB, releases GABA inside the brain and exhibit anticonvulsant activity. GABA (unable to cross BBB) Progabide ( prodrug ) 8/20/2022 Department of Pharmaceutical Chemistry 27

28. PRODRUG FOR PROLONG ACTIVITY The prodrug by its improved characteristics get closer to the receptor site for a longer period of time and conversion to the parent drug takes place at the site of action. It reduces the number and frequency of dose It eliminates night time administration of drugs Minimize patient non compliance. 8/20/2022 Department of Pharmaceutical Chemistry 28

29. Haloperidol is a potent tranquilizer and its peak plasma observed between 2-6 hrs after administration .The ester prodrug haloperidol decanoate is injected i.m . as a solution in sesame oil and its antipsychotic activity last for about 1 month . Haloperidol decanoate ( prodrug ) Haloperidol (active) 8/20/2022 Department of Pharmaceutical Chemistry 29

30. DRUG SOLUBILITY Hydrophilic or water soluble drugs are needed when parenteral or ophthalmic formulation . Drug with hydroxyl functional group can be converted to their hydrophilic form through the use of half ester such as hemi- glutarate or hemi phthalate , the other half of this acid carries sodium, potassium or amine salts and render this moiety more soluble. 8/20/2022 Department of Pharmaceutical Chemistry 30

31. methyl prednisolone methyl presdnisolone succinate ester 8/20/2022 Department of Pharmaceutical Chemistry 31

32. RATIONALE OF PRODRUG DESIGN The prodrug design includes an infixed position that can be altered to improve in membrane permeability, solubility and ADME properties. Different prodrugs used for cancer therapies and other related therapies include, Antibody directed enzyme prodrug therapy Gene directed enzyme prodrug therapy Polymer directed enzyme prodrug therapy Virus directed enzyme prodrug therapy Lectin directed enzyme prodrug therapy Clostridiol directed enzyme prodrug therapy 8/20/2022 Department of Pharmaceutical Chemistry 32

33. ANTIBODY DIRECTED ENZYME PRODRUG THERAPY In the targeted therapy , the antibody enzyme conjugate will help in selective binding of enzyme to the tumor cell and then the prodrug converts into the active drug by the targeted enzyme , thus only affecting the tumor and leaving back the normal cells. GENE DIRECTED ENZYME PRODRUG THERAPY It is a suicide gene therapy in which the enzyme required for prodrug conversion is produced within the target cell , using a gene delivered to it by gene therapy VIRUS DIRECTED ENZYME PRODRUG THERAPY It is an emerging strategy against cancer to the use of virus . It can be potentially used to enhance the therapeutic potential of oncolytic virus. 8/20/2022 Department of Pharmaceutical Chemistry 33

34. POLYMER DIRECTED ENZYME ACTIVATED PRODRUG THERAPY It is a novel two step antitumor approach using a combination of a polymeric prodrug and polymeric enzyme conjugated to generate cytotoxic drug selectivey at the tumor site. LECTIN DIRECTED ENZYME ACTIVATED PRODRUG THERAPY It is designed to exploit endogenous carbohydrate - lectin binding by combining it with biocatalysis through the construction of novel glycosylated enzymes and prodrugs . CLOSTRIDIA - DIRECTED ENZYME PRODRUG THERAPY The use of clostridia to convert prodrugs into active drug agents. It expoits the tumor using anaerobic bacteria resident in the tumor to convert the prodrug to the active form 8/20/2022 Department of Pharmaceutical Chemistry 34