PRODRUG DESIGN [M.PHARM]

THE PRODRUG DESIGNING FOR NEW SELECTION AND FORMULATION OF DRUG COMPATIBLE WITH API I.E. ACTIVE PHARMACUTICAL INGREDIENT, AND ITS EFFECT WHICH SHOULD BE 0. THE DRUG COMBINED WITH API AND AVILABLE IN MARKET AND DRUGS NEED TO BE COMBINE ARE ALSO DISCUSSED WITH ITS STRUCTURE AND SAR, AND COVERED AS PER THE SYLLABUS OF PCI.

1. PRODRUG DESIGN Presented by Shikha D. Popali Harshpal Singh Wahi M. Pharmacy 1 st semester (Pharmaceutical chemistry ) Gurunanak college of pharmacy , Nagpur

2. Overview Introduction What is prodrug & prodrug design? Objectives of prodrug design Basic concept of prodrugs Classification of prodrugs Prodrugs of functional group Why use prodrugs? Applications of prodrugs Examples Recent search Conclusion References 12/18/2019 2

3. In 1958, Albert introduced the prodrug term for the first time in his book „selective toxicity‟. This term includes any inert compound that undergoes in vivo biotransformation. Methenamine was discovered in 1899 by Schering as inactive prodrug that delivers the antibacterial formaldehyde. It is useful in the treatment of urinary tract infection, when transported to urinary bladder it becomes acidified to provide a medium in which formaldehyde is generated . Methenamine prodrug activation at acidic ph. Introduction 12/18/2019 3

4. What is prodrug & prodrug design? Prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolized in vivo into an active drug within the body through metabolic process, such as hydrolysis of an ester form of the drug. Sometimes drugs are designed to make use of metabolic processes in order to generate their active form. This is done in order to improve some selected property of the molecule, such as water solubility or ability to cross a membrane, temporarily. 12/18/2019 4

5. Objectives of prodrug design The main objectives of a prodrug designing are To bring active drugs to their respective active sites. To provide the desired pharmacological effects while minimizing adverse metabolic and/or toxicological events. To improve the clinical and therapeutic effectiveness of those drugs which suffer from some undesirable properties that otherwise hinder their clinical usefulness. To avoid the practice of clinically Coad ministering two drugs in order to enhance pharmacological activity or prevent clinical side effects. 12/18/2019 5

6. Basic concept of prodrugs The drug – promoiety is the prodrug that is typically pharmacologically inactive. Limitation of a parent drug that prevents optimal (bio)pharmaceutical or pharmacokinetic performance. The drug and promoiety are covalently linked via bio-reversible groups that are chemically or enzymatically labile. Promoiety A functional group used To modify the structure Of pharmacologically Active agents to improve Physicochemical, Biopharmaceutical or Pharmacokinetic properties . 12/18/2019 6

7. Classification of prodrugs Carrier-linked prodrugs: S imple prodrug that contains an active drug linked with a carrier group that is removed enzymatically. The carrier group must be non-toxic and biologically inactive when detached from drug. Carrier type Prodrug: formulation and drug release 12/18/2019 7

8. Carrier- linked prodrug may further be classified into: 1) Double prodrugs pro-prodrugs or cascade- latentiated prodrug Where a prodrug is futherderivatized in a fashion such that only enzymatic conversion to prodrug is possible before the latter can cleave to release the active drug. 2) Macromolecular prodrugs Where macromolecules like polysaccharides, dextrans, cyclodextrins, proteins, peptides and polymers are used as carriers. 3) Site- specific prodrugs where a carrier acts as a transporter of the active drug to a specific targeted site. 4) Mutual prodrug where the carrier used is another biologically active drug instead of some inert molecule. 12/18/2019 8

9. Bioprecursors : A compound that is metabolized by molecular modification into a new compound that may itself be active or further metabolized to an active metabolite. This prodrug does not contain carriers but ready up on metabolism to induce the necessary functionally active species. Bioprecursor prodrugs rely on oxidative or reductive activation reactions unlike the hydrolytic activation of carrier-linked prodrugs. They metabolized into a new compound that may itself be active or further metabolized to an active metabolite (e.g. Amine to aldehyde to carboxylic acid, Inactive prontosil to sulphanilamide). 12/18/2019 9

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11. Prodrugs of functional group Various types of functional groups are present in different therapeutic agents. These functional groups react with other functional groups of non toxic promoiety to form prodrugs. 1) Ester Groups like -COOH, -OH can easily undergo esterification reaction. Bioavailability of drug can be improved by ester formation. Enzyme esterase which is present widely in vivo can easily break up the linkage at target organ so that targeted delivery is achieved e.g. Thioester of Erythromycin, palmitate ester of Clindamycin. Prodrug Active Form of Drug 12/18/2019 11

12. 2) Amides The utility of the N-(acyloxy alkoxy carbonyl) derivative is limited due to the resistance to undergo enzymatic cleave in vivo. However, certain activated amides are chemically labile and also certain amides formed with amino acids may undergo enzymatic cleavage. For example the γ- glutamyl derivatives of dopamine, L-Dopa, N-glycyl derivative . N-glycyl derivative 12/18/2019 12

13. 3) Prodrugs of amides, imides and urides e.g.N-hydroxymethylation The N-hydroxyl methyl derivatives of amides or imide type compounds are more water soluble than the parent compounds. By replacing a proton bind to nitrogen atom by a hydroxyl methyl group, intra or intermolecular hydrogen bonding in such molecules may be increased resulting in a decrease in melting point and increase in water solubility The mechanism for the decomposition of N-hydroxyl methyl derivatives . 12/18/2019 13

14. 4) Ring formation derivative Thiamine quaternary ammonium compounds like Hydantoin, Barbituric acid etc. can undergo ring opening and show in vivo pharmacological properties. 5) Glycol amide esters These are bioavailable products of carboxylic group e.g. Benzoic acid esters. 6) Carbamates They exhibit restricted distribution in the body. Carbamates do not have any specific enzyme for hydrolysis. However, enzymes such as esterase can hydrolyze carbamates e.g. co- carboxy methyl phenyl ester of Amphetamine. Other approaches used in the formation of prodrug are phosphamides, glycosides, ethers , and ketals. 12/18/2019 14

15. Why use prodrugs? Improve membrane permeability Improve absorption and distribution Improve solubility Alter metabolism Alter toxicity Alter elimination 12/18/2019 15

16. Application of prodrugs Pharmaceutical applications Improvement of taste Improvement of odour Reduction of irritation Reduction of pain on injection Enhancement of drug solubility and dissolution rate Enhancement of chemical stability of drug Pharmacokinetic applications Enhancement of provability Prevention of pre-systemic metabolism Prolongation of duration of action Reduction of toxicity Site specific drug-delivery 12/18/2019 16

17. E.g. Esters Esters are the most commonly employed prodrugs. Numerous catalytic esterases are present in vivo to hydrolyze simple esters. Prodrug Active Form of Drug 12/18/2019 17

18. B. Enalapril The monoethyl ester of enalaprilat Enalaprilate was first discovered as an inhibitor of angiotensin converting enzyme (ACE) and used to treat hypertension. Due to its high polarity, it was not orally bioavailable, and thus needed to be administered by injection. 12/18/2019 18

19. Recent search Table 1. Prodrugs launched in the USA, 2013–2015 12/18/2019 19

20. Conclusion Prodrugs are inactive compounds which are converted to active drugs in the body. Prodrugs were design to improve pharmacokinetic and drug delivery properties. Esters are commonly used as prodrugs to make a drug less polar. The nature of the ester can be altered to vary the rate of hydrolysis. 12/18/2019 20

21. References Alagarsamy, V. (2010). Textbook of medicinal chemistry (vol. 1, pp. 71-79). New Delhi: reed/elsevier. Testa, b., & Mayer, J. (2003). <I>hydrolysis in drug and prodrug metabolism: chemistry, biochemistry, and enzymology</i>. Zurich: VHCA. Drug metabolism. (N.D.). Retrieved November 18, 2014, from http://www.Merckmanuals.Com/home/drugs/administration and kinetics of drugs/drug metabolism.html. Supriya shirke*, S heetal S hewale and M anik Satpute (2015) , Department of Pharmaceutics, SCOP S atara, M aharashtra, I ndia. Prodrug design: an overview international journal of pharmaceutical, chemical and biological sciences, IJPCBS 2015, 5(1), 232-241 (pp. 233-236). Prodrug design available from: file:/// I:/ prodrug/prodrug%20concept%20PPT.htm. 12/18/2019 21

22. Questions 12/18/2019 22

23. THANKS TO ALL OF U 12/18/2019 23