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Prodrugs

Prodrugs. 3 examples of prodrugs such as SIMVASTATIN, LEVODOPA, CAPECITABINE. Directed Enzyme Prodrug Therapy (DEPT).

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Prodrugs

  1. 1. Prodrugs Aman Kumar Naik Integrated M.Sc.9/11/2015 :: National Institute of Science Education and Research ::
  2. 2. OR O R1 O O R2 S R1 O O R2 Ethers S O R O OR O O R1 O O R2 Esters O O OR Carbonates O Carbamates O NHR Amides N H O P O OH O O P O OH OH O P O OH OH Phosphates –PO(OH)2 –SH –COOH –NH –OH Drug Drug PromoietyDrug Drug + Enzymatic and/or chemical transformation Barrier a b Promoiety Promoiety should be considered with respect to the disease s dose and the duration of therapy. • Parent and prodrug: the absorption, distribut metabolism, excretion (ADME) and pharmacokin properties need to be comprehensively understo • Degradation by-products: these can affect chem and physical stability and lead to the formatio new degradation products. Some of the most common functional groups tha amenable to prodrug design include carboxylic, hydro amine, phosphate/phosphonate and carbonyl gro Prodrugs typically produced via the modification of t groups include esters, carbonates, carbamates, ami phosphates and oximes. However, other uncomm functional groups have also been investigated as po tially useful structures in prodrug design. For exam thiols react in a similar manner to alcohols and ca derivatized to thioethers18 and thioesters19 . Amines bederivatizedintoimines20,21 andN-Mannichbases22 . prodrug structures for the most common functional are illustrated in FIG. 1b and discussed below. Esters as prodrugs of carboxyl, hydroxyl and thiol fu tionalities. Esters are the most common prodrugs u anditisestimatedthatapproximately49%ofallmark prodrugs are activated by enzymatic hydrolysis4 . E prodrugs are most often used to enhance the lipophili REVIEWS OR O R1 O O R2 S R1 O O R2 Ethers S O R O OR O O R1 O O R2 Esters O O OR Carbonates O Carbamates O NHR Amides N H O P O OH O O P O OH OH O P O OH OH Phosphates –PO(OH)2 –SH –COOH –NH –OH Drug Drug PromoietyDrug Drug + Enzymatic and/or chemical transformation Barrier a b Promoiety Promoiety should be considered with respect to the disease s dose and the duration of therapy. • Parent and prodrug: the absorption, distribut metabolism, excretion (ADME) and pharmacokin properties need to be comprehensively understo • Degradation by-products: these can affect chem and physical stability and lead to the formatio new degradation products. Some of the most common functional groups tha amenable to prodrug design include carboxylic, hydro amine, phosphate/phosphonate and carbonyl gro Prodrugs typically produced via the modification of t groups include esters, carbonates, carbamates, ami phosphates and oximes. However, other uncomm functional groups have also been investigated as po tially useful structures in prodrug design. For exam thiols react in a similar manner to alcohols and ca derivatized to thioethers18 and thioesters19 . Amines bederivatizedintoimines20,21 andN-Mannichbases22 . prodrug structures for the most common functional are illustrated in FIG. 1b and discussed below. Esters as prodrugs of carboxyl, hydroxyl and thiol fu tionalities. Esters are the most common prodrugs u anditisestimatedthatapproximately49%ofallmark prodrugs are activated by enzymatic hydrolysis4 . E prodrugs are most often used to enhance the lipophili REVIEWS Enzymatic and/or chemical transformation Representative illustration of the prodrug concept Pharmacologically inactive Pharmacologically active Covalently linked via bioreversible groups that are chemically or enzymatically labile OR O R1 O O R2 S R1 O O R2 Ethers S O R O OR O O R1 O O R2 Esters O O OR Carbonates O O NR Carbamates O NHR Amides N H O P O OH OH O O P O OH OH O P O OH OH Phosphates –PO(OH)2 –SH –COOH –NH –OH Drug Drug PromoietyDrug Drug + Enzymatic and/or chemical transformation Barrier a b Promoiety Promoiety should be considered with respect to the disease state, dose and the duration of therapy. • Parent and prodrug: the absorption, distribution, metabolism, excretion (ADME) and pharmacokinetic properties need to be comprehensively understood. • Degradation by-products: these can affect chemical and physical stability and lead to the formation of new degradation products. Some of the most common functional groups that are amenable to prodrug design include carboxylic, hydroxyl, amine, phosphate/phosphonate and carbonyl groups. Prodrugs typically produced via the modification of these groups include esters, carbonates, carbamates, amides, phosphates and oximes. However, other uncommon functional groups have also been investigated as poten- tially useful structures in prodrug design. For example, thiols react in a similar manner to alcohols and can be derivatized to thioethers18 and thioesters19 . Amines may bederivatizedintoimines20,21 andN-Mannichbases22 .The prodrug structures for the most common functionalities are illustrated in FIG. 1b and discussed below. Esters as prodrugs of carboxyl, hydroxyl and thiol func- tionalities. Esters are the most common prodrugs used, anditisestimatedthatapproximately49%ofallmarketed prodrugs are activated by enzymatic hydrolysis4 . Ester prodrugs are most often used to enhance the lipophilicity, and thus the passive membrane permeability, of water- soluble drugs by masking charged groups such as car- REVIEWS OR O R1 O O R2 S R1 O O R2 Ethers S O R O OR O O R1 O O R2 Esters O O OR Carbonates O O NR Carbamates O NHR Amides N H O P O OH OH O O P O OH OH O P O OH OH Phosphates –PO(OH)2 –SH –COOH –NH –OH Drug Drug PromoietyDrug Drug + Enzymatic and/or chemical transformation Barrier a b Promoiety Promoiety should be considered with dose and the duration of t • Parent and prodrug: the metabolism, excretion (AD properties need to be com • Degradation by-products and physical stability and new degradation products Some of the most common amenable to prodrug design in amine, phosphate/phosphon Prodrugs typically produced v groups include esters, carbon phosphates and oximes. Ho functional groups have also b tially useful structures in pro thiols react in a similar mann derivatized to thioethers18 and bederivatizedintoimines20,21 a prodrug structures for the mo are illustrated in FIG. 1b and di Esters as prodrugs of carboxy tionalities. Esters are the mos anditisestimatedthatapproxi prodrugs are activated by en prodrugs are most often used t and thus the passive membra soluble drugs by masking ch REVIEWS OR O R1 O O R2 S R1 O O R2 Ethers S O R O OR O O R1 O O R2 Esters O O OR Carbonates O O NR Carbamates O NHR Amides N H O P O OH OH O O P O OH OH O P O OH OH Phosphates –PO(OH)2 –SH –COOH –NH –OH Drug Drug PromoietyDrug Drug + Enzymatic and/or chemical transformation Barrier a b Promoiety Promoiety should be considered with respect to the disease dose and the duration of therapy. • Parent and prodrug: the absorption, distribu metabolism, excretion (ADME) and pharmacoki properties need to be comprehensively underst • Degradation by-products: these can affect chem and physical stability and lead to the formatio new degradation products. Some of the most common functional groups th amenable to prodrug design include carboxylic, hydr amine, phosphate/phosphonate and carbonyl gro Prodrugs typically produced via the modification of groups include esters, carbonates, carbamates, am phosphates and oximes. However, other uncom functional groups have also been investigated as p tially useful structures in prodrug design. For exam thiols react in a similar manner to alcohols and ca derivatized to thioethers18 and thioesters19 . Amines bederivatizedintoimines20,21 andN-Mannichbases22 prodrug structures for the most common functiona are illustrated in FIG. 1b and discussed below. Esters as prodrugs of carboxyl, hydroxyl and thiol tionalities. Esters are the most common prodrugs anditisestimatedthatapproximately49%ofallmark prodrugs are activated by enzymatic hydrolysis4 . prodrugs are most often used to enhance the lipophi and thus the passive membrane permeability, of w soluble drugs by masking charged groups such as REVIEWS
  3. 3. Nature Reviews | Drug Discovery OR O R1 O O R2 S R1 O O R2 Ethers S O R O OR O O R1 O O R2 Esters O O OR Carbonates O O NR Carbamates O NHR Amides N H O P O OH OH O O P O OH OH O P O OH OH Phosphates N R Imines N OR Oximes N H N O R2 R1 N-Mannich bases –PO(OH)2 –SH –COOH –NH –C O –OH Drug Drug PromoietyDrug Drug + Enzymatic and/or chemical transformation Barrier a b Promoiety Promoiety should be considered with respect to the disease state, dose and the duration of therapy. • Parent and prodrug: the absorption, distribution, metabolism, excretion (ADME) and pharmacokinetic properties need to be comprehensively understood. • Degradation by-products: these can affect chemical and physical stability and lead to the formation of new degradation products. Some of the most common functional groups that are amenable to prodrug design include carboxylic, hydroxyl, amine, phosphate/phosphonate and carbonyl groups. Prodrugs typically produced via the modification of these groups include esters, carbonates, carbamates, amides, phosphates and oximes. However, other uncommon functional groups have also been investigated as poten- tially useful structures in prodrug design. For example, thiols react in a similar manner to alcohols and can be derivatized to thioethers18 and thioesters19 . Amines may bederivatizedintoimines20,21 andN-Mannichbases22 .The prodrug structures for the most common functionalities are illustrated in FIG. 1b and discussed below. Esters as prodrugs of carboxyl, hydroxyl and thiol func- tionalities. Esters are the most common prodrugs used, anditisestimatedthatapproximately49%ofallmarketed prodrugs are activated by enzymatic hydrolysis4 . Ester prodrugs are most often used to enhance the lipophilicity, and thus the passive membrane permeability, of water- soluble drugs by masking charged groups such as car- boxylic acids and phosphates3,23 . The synthesis of an ester prodrug is often straightforward. Once in the body, the ester bond is readily hydrolysed by ubiquitous esterases found in the blood, liver and other organs and tissues24 , including carboxylesterases, acetylcholinesterases, butyrylcholinesterases, paraoxonases and arylesterases. However, one significant challenge with ester prodrugs is the accurate prediction of pharmacokinetic disposition in humans, owing to significant differences in specific carboxylesterase activities in preclinical species25 , as reported for the exploratory intravenous diester pro- drug of nalbuphine26 . A comprehensive review on ester Figure 1 | A simplified representative illustration of the prodrug concept. a | The drug–promoiety is the prodrug that is typically pharmacologically inactive. In broad terms, the barrier can be thought of as any liability or limitation of a parent drug that prevents optimal (bio)pharmaceutical or pharmacokinetic performance, and which Nature Reviews | Drug Discovery OR O R1 O O R2 S R1 O O R2 Ethers S O R O OR O O R1 O O R2 Esters O O OR Carbonates O O NR Carbamates O NHR Amides N H O P O OH OH O O P O OH OH O P O OH OH Phosphates N R Imines N OR Oximes N H N O R2 R1 N-Mannich bases –PO(OH)2 –SH –COOH –NH –C O –OH Drug Drug PromoietyDrug + Barrier b Promoiety Promoiety and physical stability and lead to the formation of new degradation products. Some of the most common functional groups that are amenable to prodrug design include carboxylic, hydroxyl, amine, phosphate/phosphonate and carbonyl groups. Prodrugs typically produced via the modification of these groups include esters, carbonates, carbamates, amides, phosphates and oximes. However, other uncommon functional groups have also been investigated as poten- tially useful structures in prodrug design. For example, thiols react in a similar manner to alcohols and can be derivatized to thioethers18 and thioesters19 . Amines may bederivatizedintoimines20,21 andN-Mannichbases22 .The prodrug structures for the most common functionalities are illustrated in FIG. 1b and discussed below. Esters as prodrugs of carboxyl, hydroxyl and thiol func- tionalities. Esters are the most common prodrugs used, anditisestimatedthatapproximately49%ofallmarketed prodrugs are activated by enzymatic hydrolysis4 . Ester prodrugs are most often used to enhance the lipophilicity, and thus the passive membrane permeability, of water- soluble drugs by masking charged groups such as car- boxylic acids and phosphates3,23 . The synthesis of an ester prodrug is often straightforward. Once in the body, the ester bond is readily hydrolysed by ubiquitous esterases found in the blood, liver and other organs and tissues24 , including carboxylesterases, acetylcholinesterases, butyrylcholinesterases, paraoxonases and arylesterases. However, one significant challenge with ester prodrugs is the accurate prediction of pharmacokinetic disposition in humans, owing to significant differences in specific carboxylesterase activities in preclinical species25 , as reported for the exploratory intravenous diester pro- drug of nalbuphine26 . A comprehensive review on ester prodrugs that enhance oral absorption of predominantly poorly permeable and polar parent drugs was recently published by Beaumont et al.3 Several alkyl and aryl ester prodrugs are in clinical use3 , of which angiotensin-converting enzyme (ACE) 24 Figure 1 | A simplified representative illustration of the prodrug concept. a | The drug–promoiety is the prodrug that is typically pharmacologically inactive. In broad terms, the barrier can be thought of as any liability or limitation of a parent drug that prevents optimal (bio)pharmaceutical or pharmacokinetic performance, and which has to be overcome for the development of a marketable drug. The drug and promoiety are covalently linked via bioreversible groups that are chemically or enzymatically labile, such as those shown here. The ‘ideal’ prodrug yields the parent drug with high recovery ratios, with the promoiety being non-toxic. b | Common functional groups on parent drugs that are amenable to prodrug design (shown in green). Most prodrug approaches require a ‘synthetic handle’ on the drug, which are typically heteroatomic groups. Nature Reviews | Drug Discovery OR O R1 O O R2 S R1 O O R2 Ethers S O R O OR O O R1 O O R2 Esters O O OR Carbonates O O NR Carbamates O NHR Amides N H O P O OH OH O O P O OH OH O P O OH OH Phosphates N R Imines N OR Oximes N H N O R2 R1 N-Mannich bases –PO(OH)2 –SH –COOH –NH –C O –OH Drug Drug PromoietyDrug Drug + Enzymatic and/or chemical transformation Barrier a b Promoiety Promoiety should be considered with respect to the disease stat dose and the duration of therapy. • Parent and prodrug: the absorption, distributio metabolism, excretion (ADME) and pharmacokinet properties need to be comprehensively understood • Degradation by-products: these can affect chemic and physical stability and lead to the formation new degradation products. Some of the most common functional groups that a amenable to prodrug design include carboxylic, hydrox amine, phosphate/phosphonate and carbonyl group Prodrugs typically produced via the modification of the groups include esters, carbonates, carbamates, amide phosphates and oximes. However, other uncommo functional groups have also been investigated as pote tially useful structures in prodrug design. For examp thiols react in a similar manner to alcohols and can b derivatized to thioethers18 and thioesters19 . Amines m bederivatizedintoimines20,21 andN-Mannichbases22 .Th prodrug structures for the most common functionaliti are illustrated in FIG. 1b and discussed below. Esters as prodrugs of carboxyl, hydroxyl and thiol fun tionalities. Esters are the most common prodrugs use anditisestimatedthatapproximately49%ofallmarkete prodrugs are activated by enzymatic hydrolysis4 . Est prodrugs are most often used to enhance the lipophilici and thus the passive membrane permeability, of wate soluble drugs by masking charged groups such as ca boxylic acids and phosphates3,23 . The synthesis of an est prodrug is often straightforward. Once in the body, th ester bond is readily hydrolysed by ubiquitous esteras found in the blood, liver and other organs and tissues including carboxylesterases, acetylcholinesterase butyrylcholinesterases, paraoxonases and arylesterase However, one significant challenge with ester prodrugs the accurate prediction of pharmacokinetic dispositio in humans, owing to significant differences in specif carboxylesterase activities in preclinical species25 , reported for the exploratory intravenous diester pr drug of nalbuphine26 . A comprehensive review on est Figure 1 | A simplified representative illustration of the prodrug concept. a | The drug–promoiety is the prodrug that is typically pharmacologically inactive. In broad terms, the barrier can be thought of as any liability or limitation of a parent drug that prevents optimal (bio)pharmaceutical or pharmacokinetic performance, and which Nature Reviews | Drug Discovery OR O R1 O O R2 S R1 O O R2 Ethers S O R O OR O O R1 O O R2 Esters O O OR Carbonates O O NR Carbamates O NHR Amides N H O P O OH OH O O P O OH OH O P O OH OH Phosphates N R Imines N OR Oximes N H N O R2 R1 N-Mannich bases –PO(OH)2 –SH –COOH –NH –C O –OH Drug Drug PromoietyDrug Drug + and/or chemical transformation Barrier b Promoiety Promoiety • Parent and prodrug: the absorption, distribution, metabolism, excretion (ADME) and pharmacokinetic properties need to be comprehensively understood. • Degradation by-products: these can affect chemical and physical stability and lead to the formation of new degradation products. Some of the most common functional groups that are amenable to prodrug design include carboxylic, hydroxyl, amine, phosphate/phosphonate and carbonyl groups. Prodrugs typically produced via the modification of these groups include esters, carbonates, carbamates, amides, phosphates and oximes. However, other uncommon functional groups have also been investigated as poten- tially useful structures in prodrug design. For example, thiols react in a similar manner to alcohols and can be derivatized to thioethers18 and thioesters19 . Amines may bederivatizedintoimines20,21 andN-Mannichbases22 .The prodrug structures for the most common functionalities are illustrated in FIG. 1b and discussed below. Esters as prodrugs of carboxyl, hydroxyl and thiol func- tionalities. Esters are the most common prodrugs used, anditisestimatedthatapproximately49%ofallmarketed prodrugs are activated by enzymatic hydrolysis4 . Ester prodrugs are most often used to enhance the lipophilicity, and thus the passive membrane permeability, of water- soluble drugs by masking charged groups such as car- boxylic acids and phosphates3,23 . The synthesis of an ester prodrug is often straightforward. Once in the body, the ester bond is readily hydrolysed by ubiquitous esterases found in the blood, liver and other organs and tissues24 , including carboxylesterases, acetylcholinesterases, butyrylcholinesterases, paraoxonases and arylesterases. However, one significant challenge with ester prodrugs is the accurate prediction of pharmacokinetic disposition in humans, owing to significant differences in specific carboxylesterase activities in preclinical species25 , as reported for the exploratory intravenous diester pro- drug of nalbuphine26 . A comprehensive review on ester prodrugs that enhance oral absorption of predominantly poorly permeable and polar parent drugs was recently Figure 1 | A simplified representative illustration of the prodrug concept. a | The drug–promoiety is the prodrug that is typically pharmacologically inactive. In broad terms, the barrier can be thought of as any liability or limitation of a parent drug that prevents optimal (bio)pharmaceutical or pharmacokinetic performance, and which has to be overcome for the development of a marketable drug. The drug and promoiety are covalently linked via bioreversible groups that are chemically or enzymatically labile, Nature Reviews | Drug Discovery OR O R1 O O R2 S R1 O O R2 Ethers S O R O OR O O R1 O O R2 Esters O O OR Carbonates O O NR Carbamates O NHR Amides N H O P O OH OH O O P O OH OH O P O OH OH Phosphates N R Imines N OR Oximes N H N O R2 R1 N-Mannich bases –PO(OH)2 –SH –COOH –NH –C O –OH Drug Drug PromoietyDrug + Barrier b Promoiety Promoiety • Degradation by-products: these can affect chemical and physical stability and lead to the formation of new degradation products. Some of the most common functional groups that are amenable to prodrug design include carboxylic, hydroxyl, amine, phosphate/phosphonate and carbonyl groups. Prodrugs typically produced via the modification of these groups include esters, carbonates, carbamates, amides, phosphates and oximes. However, other uncommon functional groups have also been investigated as poten- tially useful structures in prodrug design. For example, thiols react in a similar manner to alcohols and can be derivatized to thioethers18 and thioesters19 . Amines may bederivatizedintoimines20,21 andN-Mannichbases22 .The prodrug structures for the most common functionalities are illustrated in FIG. 1b and discussed below. Esters as prodrugs of carboxyl, hydroxyl and thiol func- tionalities. Esters are the most common prodrugs used, anditisestimatedthatapproximately49%ofallmarketed prodrugs are activated by enzymatic hydrolysis4 . Ester prodrugs are most often used to enhance the lipophilicity, and thus the passive membrane permeability, of water- soluble drugs by masking charged groups such as car- boxylic acids and phosphates3,23 . The synthesis of an ester prodrug is often straightforward. Once in the body, the ester bond is readily hydrolysed by ubiquitous esterases found in the blood, liver and other organs and tissues24 , including carboxylesterases, acetylcholinesterases, butyrylcholinesterases, paraoxonases and arylesterases. However, one significant challenge with ester prodrugs is the accurate prediction of pharmacokinetic disposition in humans, owing to significant differences in specific carboxylesterase activities in preclinical species25 , as reported for the exploratory intravenous diester pro- drug of nalbuphine26 . A comprehensive review on ester prodrugs that enhance oral absorption of predominantly poorly permeable and polar parent drugs was recently published by Beaumont et al.3 Several alkyl and aryl ester prodrugs are in clinical Figure 1 | A simplified representative illustration of the prodrug concept. a | The drug–promoiety is the prodrug that is typically pharmacologically inactive. In broad terms, the barrier can be thought of as any liability or limitation of a parent drug that prevents optimal (bio)pharmaceutical or pharmacokinetic performance, and which has to be overcome for the development of a marketable drug. The drug and promoiety are covalently linked via bioreversible groups that are chemically or enzymatically labile, such as those shown here. The ‘ideal’ prodrug yields the parent drug with high recovery ratios, with the promoiety being non-toxic. b | Common functional groups on parent drugs that are amenable to prodrug design (shown in green). Most prodrug approachesNature Reviews | Drug Discovery OR O R1 O O R2 S R1 O O R2 Ethers S O R O OR O O R1 O O R2 Esters O O OR Carbonates O O NR Carbamates O NHR Amides N H O P O OH OH O O P O OH OH O P O OH OH Phosphates N R Imines N OR Oximes N H N O R2 R1 N-Mannich bases –PO(OH)2 –SH –COOH –NH –C O –OH Drug Drug PromoietyDrug Drug + Enzymatic and/or chemical transformation Barrier a b Promoiety Promoiety should be considered with respect to the dise dose and the duration of therapy. • Parent and prodrug: the absorption, distr metabolism, excretion (ADME) and pharma properties need to be comprehensively und • Degradation by-products: these can affect and physical stability and lead to the form new degradation products. Some of the most common functional group amenable to prodrug design include carboxylic, amine, phosphate/phosphonate and carbony Prodrugs typically produced via the modification groups include esters, carbonates, carbamates phosphates and oximes. However, other unc functional groups have also been investigated a tially useful structures in prodrug design. For thiols react in a similar manner to alcohols an derivatized to thioethers18 and thioesters19 . Am bederivatizedintoimines20,21 andN-Mannichba prodrug structures for the most common funct are illustrated in FIG. 1b and discussed below. Esters as prodrugs of carboxyl, hydroxyl and th tionalities. Esters are the most common prodru anditisestimatedthatapproximately49%ofallm prodrugs are activated by enzymatic hydrolys prodrugs are most often used to enhance the lipo and thus the passive membrane permeability, soluble drugs by masking charged groups suc boxylic acids and phosphates3,23 . The synthesis o prodrug is often straightforward. Once in the b ester bond is readily hydrolysed by ubiquitous found in the blood, liver and other organs and including carboxylesterases, acetylcholine butyrylcholinesterases, paraoxonases and aryle However, one significant challenge with ester pr the accurate prediction of pharmacokinetic di in humans, owing to significant differences in carboxylesterase activities in preclinical spe reported for the exploratory intravenous die Figure 1 | A simplified representative illustration of the prodrug concept. a | The drug–promoiety is the prodrug that is typically pharmacologically inactive. In broad terms, the barrier can be thought of as any liability or limitation of a parent drug Nature Reviews | Drug Discovery OR O R1 O O R2 S R1 O O R2 Ethers S O R O OR O O R1 O O R2 Esters O O OR Carbonates O O NR Carbamates O NHR Amides N H O P O OH OH O O P O OH OH O P O OH OH Phosphates N R Imines N OR Oximes N H N O R2 R1 N-Mannich bases –PO(OH)2 –SH –COOH –NH –C O –OH Drug Drug PromoietyDrug Drug + Enzymatic and/or chemical transformation Barrier b Promoiety Promoiety dose and the duration of therapy. • Parent and prodrug: the absorption, distr metabolism, excretion (ADME) and pharmac properties need to be comprehensively unde • Degradation by-products: these can affect c and physical stability and lead to the form new degradation products. Some of the most common functional group amenable to prodrug design include carboxylic, h amine, phosphate/phosphonate and carbonyl Prodrugs typically produced via the modification groups include esters, carbonates, carbamates, phosphates and oximes. However, other unc functional groups have also been investigated a tially useful structures in prodrug design. For e thiols react in a similar manner to alcohols an derivatized to thioethers18 and thioesters19 . Ami bederivatizedintoimines20,21 andN-Mannichbas prodrug structures for the most common functi are illustrated in FIG. 1b and discussed below. Esters as prodrugs of carboxyl, hydroxyl and th tionalities. Esters are the most common prodru anditisestimatedthatapproximately49%ofallm prodrugs are activated by enzymatic hydrolys prodrugs are most often used to enhance the lipo and thus the passive membrane permeability, o soluble drugs by masking charged groups suc boxylic acids and phosphates3,23 . The synthesis o prodrug is often straightforward. Once in the b ester bond is readily hydrolysed by ubiquitous found in the blood, liver and other organs and including carboxylesterases, acetylcholines butyrylcholinesterases, paraoxonases and aryle However, one significant challenge with ester pro the accurate prediction of pharmacokinetic dis in humans, owing to significant differences in carboxylesterase activities in preclinical spec reported for the exploratory intravenous dies drug of nalbuphine26 . A comprehensive review prodrugs that enhance oral absorption of predom Figure 1 | A simplified representative illustration of the prodrug concept. a | The drug–promoiety is the prodrug that is typically pharmacologically inactive. In broad terms, the barrier can be thought of as any liability or limitation of a parent drug that prevents optimal (bio)pharmaceutical or pharmacokinetic performance, and which has to be overcome for the development of a marketable drug. The drug and promoiety Nature Reviews | Drug Discovery OR O R1 O O R2 S R1 O O R2 Ethers S O R O OR O O R1 O O R2 Esters O O OR Carbonates O O NR Carbamates O NHR Amides N H O P O OH OH O O P O OH OH O P O OH OH Phosphates N R Imines N OR Oximes N H N O R2 R1 N-Mannich bases –PO(OH)2 –SH –COOH –NH –C O –OH Drug Drug PromoietyDrug + transformation Barrier b Promoiety Promoiety metabolism, excretion (ADME) and pharmac properties need to be comprehensively unde • Degradation by-products: these can affect c and physical stability and lead to the form new degradation products. Some of the most common functional groups amenable to prodrug design include carboxylic, h amine, phosphate/phosphonate and carbonyl Prodrugs typically produced via the modification groups include esters, carbonates, carbamates, phosphates and oximes. However, other unc functional groups have also been investigated a tially useful structures in prodrug design. For e thiols react in a similar manner to alcohols an derivatized to thioethers18 and thioesters19 . Ami bederivatizedintoimines20,21 andN-Mannichbas prodrug structures for the most common functi are illustrated in FIG. 1b and discussed below. Esters as prodrugs of carboxyl, hydroxyl and th tionalities. Esters are the most common prodru anditisestimatedthatapproximately49%ofallm prodrugs are activated by enzymatic hydrolysi prodrugs are most often used to enhance the lipo and thus the passive membrane permeability, o soluble drugs by masking charged groups such boxylic acids and phosphates3,23 . The synthesis o prodrug is often straightforward. Once in the b ester bond is readily hydrolysed by ubiquitous e found in the blood, liver and other organs and including carboxylesterases, acetylcholines butyrylcholinesterases, paraoxonases and aryle However, one significant challenge with ester pro the accurate prediction of pharmacokinetic dis in humans, owing to significant differences in carboxylesterase activities in preclinical spec reported for the exploratory intravenous dies drug of nalbuphine26 . A comprehensive review prodrugs that enhance oral absorption of predom poorly permeable and polar parent drugs was published by Beaumont et al.3 Figure 1 | A simplified representative illustration of the prodrug concept. a | The drug–promoiety is the prodrug that is typically pharmacologically inactive. In broad terms, the barrier can be thought of as any liability or limitation of a parent drug that prevents optimal (bio)pharmaceutical or pharmacokinetic performance, and which has to be overcome for the development of a marketable drug. The drug and promoiety are covalently linked via bioreversible groups that are chemically or enzymatically labile, such as those shown here. The ‘ideal’ prodrug yields the parent drug with high recovery Nature Reviews | Drug Discovery OR O R1 O O R2 S R1 O O R2 Ethers S O R O OR O O R1 O O R2 Esters O O OR Carbonates O O NR Carbamates O NHR Amides N H O P O OH OH O O P O OH OH O P O OH OH Phosphates N R Imines N OR Oximes N H N O R2 R1 N-Mannich bases –PO(OH)2 –SH –COOH –NH –C O –OH Barrier b new degradation products. Some of the most common functional group amenable to prodrug design include carboxylic, h amine, phosphate/phosphonate and carbonyl Prodrugs typically produced via the modification groups include esters, carbonates, carbamates, phosphates and oximes. However, other unc functional groups have also been investigated a tially useful structures in prodrug design. For e thiols react in a similar manner to alcohols an derivatized to thioethers18 and thioesters19 . Am bederivatizedintoimines20,21 andN-Mannichbas prodrug structures for the most common functi are illustrated in FIG. 1b and discussed below. Esters as prodrugs of carboxyl, hydroxyl and th tionalities. Esters are the most common prodru anditisestimatedthatapproximately49%ofallm prodrugs are activated by enzymatic hydrolys prodrugs are most often used to enhance the lipo and thus the passive membrane permeability, o soluble drugs by masking charged groups suc boxylic acids and phosphates3,23 . The synthesis o prodrug is often straightforward. Once in the b ester bond is readily hydrolysed by ubiquitous found in the blood, liver and other organs and including carboxylesterases, acetylcholines butyrylcholinesterases, paraoxonases and aryle However, one significant challenge with ester pro the accurate prediction of pharmacokinetic dis in humans, owing to significant differences in carboxylesterase activities in preclinical spe reported for the exploratory intravenous dies drug of nalbuphine26 . A comprehensive review prodrugs that enhance oral absorption of predom poorly permeable and polar parent drugs was published by Beaumont et al.3 Several alkyl and aryl ester prodrugs are in use3 , of which angiotensin-converting enzym inhibitors are some of the most successful2 representative sample shown in TABLE 1. How Figure 1 | A simplified representative illustration of the prodrug concept. a | The drug–promoiety is the prodrug that is typically pharmacologically inactive. In broad terms, the barrier can be thought of as any liability or limitation of a parent drug that prevents optimal (bio)pharmaceutical or pharmacokinetic performance, and which has to be overcome for the development of a marketable drug. The drug and promoiety are covalently linked via bioreversible groups that are chemically or enzymatically labile, such as those shown here. The ‘ideal’ prodrug yields the parent drug with high recovery ratios, with the promoiety being non-toxic. b | Common functional groups on parent drugs that are amenable to prodrug design (shown in green). Most prodrug approaches require a ‘synthetic handle’ on the drug, which are typically heteroatomic groups. OR O R1 O O R2 S R1 O O R2 Ethers S O R O OR O O R1 O O R2 Esters O O OR Carbonates O O NR Carbamates O NHR Amides N H O P O OH OH O O P O OH OH O P O OH OH Phosphates N R Imines N OR Oximes N H N O R2 R1 N-Mannich bases –PO(OH)2 –SH –COOH –NH –C O –OH Drug Drug PromoietyDrug Drug + Enzymatic and/or chemical transformation Barrier a b Promoiety Promoiety should be considered with respect to the disease s dose and the duration of therapy. • Parent and prodrug: the absorption, distribut metabolism, excretion (ADME) and pharmacokin properties need to be comprehensively understo • Degradation by-products: these can affect chem and physical stability and lead to the formatio new degradation products. Some of the most common functional groups tha amenable to prodrug design include carboxylic, hydro amine, phosphate/phosphonate and carbonyl gro Prodrugs typically produced via the modification of t groups include esters, carbonates, carbamates, ami phosphates and oximes. However, other uncomm functional groups have also been investigated as po tially useful structures in prodrug design. For exam thiols react in a similar manner to alcohols and ca derivatized to thioethers18 and thioesters19 . Amines bederivatizedintoimines20,21 andN-Mannichbases22 . prodrug structures for the most common functional are illustrated in FIG. 1b and discussed below. Esters as prodrugs of carboxyl, hydroxyl and thiol fu tionalities. Esters are the most common prodrugs u anditisestimatedthatapproximately49%ofallmark prodrugs are activated by enzymatic hydrolysis4 . E prodrugs are most often used to enhance the lipophili and thus the passive membrane permeability, of wa soluble drugs by masking charged groups such as boxylic acids and phosphates3,23 . The synthesis of an e prodrug is often straightforward. Once in the body ester bond is readily hydrolysed by ubiquitous ester found in the blood, liver and other organs and tissu including carboxylesterases, acetylcholinestera butyrylcholinesterases, paraoxonases and arylestera However, one significant challenge with ester prodru the accurate prediction of pharmacokinetic disposi REVIEWS Nature Reviews | Drug Discovery OR O R1 O O R2 S R1 O O R2 Ethers S O R O OR O O R1 O O R2 Esters O O OR Carbonates O O NR Carbamates O NHR Amides N H O P O OH OH O O P O OH OH O P O OH OH Phosphates N R Imines N OR Oximes N H N O R2 R1 N-Mannich bases –PO(OH)2 –SH –COOH –NH –C O –OH Barrier b new degradation products. Some of the most common funct amenable to prodrug design include amine, phosphate/phosphonate an Prodrugs typically produced via the m groups include esters, carbonates, c phosphates and oximes. However functional groups have also been in tially useful structures in prodrug d thiols react in a similar manner to derivatized to thioethers18 and thioe bederivatizedintoimines20,21 andN-M prodrug structures for the most com are illustrated in FIG. 1b and discusse Esters as prodrugs of carboxyl, hydr tionalities. Esters are the most com anditisestimatedthatapproximately prodrugs are activated by enzymat prodrugs are most often used to enha and thus the passive membrane pe soluble drugs by masking charged boxylic acids and phosphates3,23 . The prodrug is often straightforward. O ester bond is readily hydrolysed by found in the blood, liver and other including carboxylesterases, ace butyrylcholinesterases, paraoxonas However, one significant challenge w the accurate prediction of pharmac in humans, owing to significant di carboxylesterase activities in prec reported for the exploratory intra drug of nalbuphine26 . A comprehen prodrugs that enhance oral absorpti poorly permeable and polar paren published by Beaumont et al.3 Several alkyl and aryl ester pro use3 , of which angiotensin-conver inhibitors are some of the most representative sample shown in TA Figure 1 | A simplified representative illustration of the prodrug concept. a | The drug–promoiety is the prodrug that is typically pharmacologically inactive. In broad terms, the barrier can be thought of as any liability or limitation of a parent drug that prevents optimal (bio)pharmaceutical or pharmacokinetic performance, and which has to be overcome for the development of a marketable drug. The drug and promoiety are covalently linked via bioreversible groups that are chemically or enzymatically labile, such as those shown here. The ‘ideal’ prodrug yields the parent drug with high recovery ratios, with the promoiety being non-toxic. b | Common functional groups on parent drugs that are amenable to prodrug design (shown in green). Most prodrug approaches require a ‘synthetic handle’ on the drug, which are typically heteroatomic groups. Nature Reviews | Drug Discovery OR O R1 O O R2 S R1 O O R2 Ethers S O R O OR O O R1 O O R2 Esters O O OR Carbonates O O NR Carbamates O NHR Amides N H O P O OH OH O O P O OH OH O P O OH OH Phosphates N R Imines N OR Oximes N H N O R2 R1 N-Mannich bases –PO(OH)2 –SH –COOH –NH –C O –OH Drug Drug PromoietyDrug + Barrier b Promoiety Promoiety • Degradation by-products: th and physical stability and le new degradation products. Some of the most common fu amenable to prodrug design inclu amine, phosphate/phosphonate Prodrugs typically produced via th groups include esters, carbonate phosphates and oximes. Howe functional groups have also been tially useful structures in prodru thiols react in a similar manner derivatized to thioethers18 and th bederivatizedintoimines20,21 and prodrug structures for the most c are illustrated in FIG. 1b and discu Esters as prodrugs of carboxyl, h tionalities. Esters are the most co anditisestimatedthatapproxima prodrugs are activated by enzym prodrugs are most often used to e and thus the passive membrane soluble drugs by masking charg boxylic acids and phosphates3,23 . T prodrug is often straightforward ester bond is readily hydrolysed found in the blood, liver and oth including carboxylesterases, a butyrylcholinesterases, paraoxon However, one significant challeng the accurate prediction of pharm in humans, owing to significant carboxylesterase activities in p reported for the exploratory in drug of nalbuphine26 . A compreh prodrugs that enhance oral absor poorly permeable and polar par published by Beaumont et al.3 Several alkyl and aryl ester p use3 , of which angiotensin-conv Figure 1 | A simplified representative illustration of the prodrug concept. a | The drug–promoiety is the prodrug that is typically pharmacologically inactive. In broad terms, the barrier can be thought of as any liability or limitation of a parent drug that prevents optimal (bio)pharmaceutical or pharmacokinetic performance, and which has to be overcome for the development of a marketable drug. The drug and promoiety are covalently linked via bioreversible groups that are chemically or enzymatically labile, such as those shown here. The ‘ideal’ prodrug yields the parent drug with high recovery ratios, with the promoiety being non-toxic. b | Common functional groups on parent drugs that are amenable to prodrug design (shown in green). Most prodrug approaches require a ‘synthetic handle’ on the drug, which are typically heteroatomic groups. OR O R1 O O R2 S R1 O O R2 Ethers S O R O OR O O R1 O O R2 Esters O O OR Carbonates O O NR Carbamates O NHR Amides N H O P O OH OH O O P O OH OH O P O OH OH Phosphates N R Imines N OR Oximes N H N O R2 R1 N-Mannich bases –PO(OH)2 –SH –COOH –NH –C O –OH Drug Drug PromoietyDrug Drug + Enzymatic and/or chemical transformation Barrier a b Promoiety Promoiety should be considered with respect to the disease dose and the duration of therapy. • Parent and prodrug: the absorption, distribu metabolism, excretion (ADME) and pharmacoki properties need to be comprehensively underst • Degradation by-products: these can affect chem and physical stability and lead to the formatio new degradation products. Some of the most common functional groups th amenable to prodrug design include carboxylic, hydr amine, phosphate/phosphonate and carbonyl gro Prodrugs typically produced via the modification of groups include esters, carbonates, carbamates, am phosphates and oximes. However, other uncom functional groups have also been investigated as p tially useful structures in prodrug design. For exam thiols react in a similar manner to alcohols and ca derivatized to thioethers18 and thioesters19 . Amines bederivatizedintoimines20,21 andN-Mannichbases22 prodrug structures for the most common functiona are illustrated in FIG. 1b and discussed below. Esters as prodrugs of carboxyl, hydroxyl and thiol tionalities. Esters are the most common prodrugs anditisestimatedthatapproximately49%ofallmar prodrugs are activated by enzymatic hydrolysis4 . prodrugs are most often used to enhance the lipophi and thus the passive membrane permeability, of w soluble drugs by masking charged groups such as boxylic acids and phosphates3,23 . The synthesis of an prodrug is often straightforward. Once in the bod ester bond is readily hydrolysed by ubiquitous este found in the blood, liver and other organs and tiss including carboxylesterases, acetylcholinester butyrylcholinesterases, paraoxonases and arylester However, one significant challenge with ester prodr the accurate prediction of pharmacokinetic dispos in humans, owing to significant differences in sp carboxylesterase activities in preclinical species Figure 1 | A simplified representative illustration of the prodrug concept. a | The drug–promoiety is the prodrug that is typically pharmacologically inactive. Common functional groups on parent drugs that are amenable to prodrug design
  4. 4. Chemical bond Enzymes Esters Esterase found in the blood, liver and other organs and tissues i.e 1. Carboxylesterases 2. Acetylcholinesterases 3. Butyrylcholinesterases 4. Paraoxonases 5. Arylesterases Phosphate esters Phosphatase present at the intestinal brush border or in liver 1. Carbonates 2. Carbamates Esterase Amides 1. Carboxylesterase 2. Peptidase 3. Protease Oximes Versatile microsomal Cytochrome P450 (CYP450) enzymes Enzymes responsible for cleaving of a particular chemical bond
  5. 5. SIMVASTATIN [(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] 2,2-dimethylbutanoate Chemical Structure Molecular Formula: Molecular Weight : C25H38O5 418.56622 g/mol Therapeutic area : Hypercholesterolaemia
  6. 6. Side effects • Increased urination • Joint pain • Loss of consciousness • Lower back or side pain • Nasal congestion • Nausea • Runny nose • Sneezing • Sore throat • Stomachache • Sweating • Swollen joints • Troubled breathing • Weight loss • Vomiting • Dizziness • Fainting • Bladder pain • Bloody or cloudy urine • Blurred vision • Body aches or pain • Cough • Dark-colored urine • Difficult, burning, or painful urination • Difficulty with breathing • Dry mouth • Ear congestion • Fever • Dry skin • Headache • Increased hunger • Increased thirst Synthetic, SemisyntheticSource : Class : Statins Route of Administration : Tablet Prodrug Type: IA
  7. 7. Simvastatin Metabolite active openacid Estereases, Paraoxonases Non-enzymatic hydrolysis Statin open acid Oxidation(P450s) Binds to HMG CoA reductase Inhibit synthesis of Mevalonic Acid Cholesterol Mechanism of Action
  8. 8. Constituent chemicals Brand name Simvastatin Zocor Ezetimibe+Simvastatin Vytorin Niacin+Simvastatin Simcor Simvastatin+Sitagliptin Juvisync Trade Names
  9. 9. LEVODOPA Chemical Structure (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid Molecular Formula: Molecular Weight : C9H11NO4 197.18794 g/mol Therapeutic area : Parkinson’s Disease
  10. 10. Sources Mucuna pruriens Velvet bean Vicia faba Broadbean, Horsebean Phanera Orchid tree Cassia Golden shower tree Canavalia Jack bean Plant Sources
  11. 11. Sources Enzymatic Synthesis 1. Catechol 2. Sodium pyruvate 3. Ammonium acetate Mushroom tyrosinase L-Dopa Fungal Source 1. L-tyrosine 2. Lascorbic acid Fungal mycelia under optimized condition L-Dopa Bacterial Source Recombinant Escherichia herbicola L-Dopa Mutant transcripttional regulator TyrR Having Synthesis Class : Dopaminergic antiparkinsonism agents Prodrug Type : IA
  12. 12. Mechanism of Action Parkinson's disease Neurodegeneration of the extrapyramidal nervous system Affect the mobility and control of the skeletal muscular system Depletion of dopamine in the corpus striatum Dopamine Levodopa blood-brain barrier Dopamineblood-brain barrier levodopa Decarboxylase CNS
  13. 13. • Dizziness • Loss of appetite • Diarrhea • Dry mouth • Mouth and throat pain • Constipation • Change in sense of taste • Forgetfulness or confusion • Nervousness • Nightmares • Difficulty falling asleep or staying asleep • Headache • Weakness Side effects Formulations available Constituent chemicals Brand name Carbidopa + Levodopa Duopa, Rytary, Parcopa, Sinemet Carbidopa + Levodopa + Entacapone Stalevo
  14. 14. CAPECITABINE Chemical Structure Pentyl N-[1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]carbamate Molecular Weight : Molecular Formula: 359.350083 g/mol C15H22FN3O6 Therapeutic area : Cancer Treatment
  15. 15. Side effects • Nausea • Vomiting • Loss of appetite • Constipation • Tiredness, weakness • Back/joint/muscle pain • Headache • Trouble sleeping • Skin darkening or dry/itchy skin • Nausea and vomiting • Changes in diet and lifestyle • Temporary hair loss(hair growth return after treatment) SyntheticSource : Class : Antimetabolite Route of Administration : Oral: Tablets Prodrug Type : IIA
  16. 16. INTESTINE Capecitabine LIVER Capecitabine 5’-DFCR Cytidine deaminase 5’--DFUR FU liver carboxylesterase TUMOR 5’-DFCR Cytidine deaminase 5’--DFUR Thymidine phosphorylase Mechanism of Action *Thymidine phosphorylase 10 times more activated in Tumor cells
  17. 17. Dosage (mg) Brand Name 500 Capegard, Capget, Capehope, Capiibine(500 mg),Capres, Capscare(500mg) , Captabin, Capxcel, Distamine(500mg), Naprocap , Xabine, Xabine , Xeloda 250 Xelocel 150 Capres (150 mg), Distamine (150mg), Capiibine Trade Names & Dosage
  18. 18. Directed Enzyme Prodrug Therapy (DEPT) Desired Location For Drug Targeting Enzyme Artificial Incorporation of Enzym e 5 Types Enzyme
  19. 19. 1. Antibody-directed enzyme prodrug therapy (ADEPT) 2. Gene-directed enzyme prodrug therapy (GDEPT) Enzyme
  20. 20. 3. Virus-directed enzyme prodrug therapy (VDEPT) 4. Polymer-directed enzyme prodrug therapy (PDEPT)
  21. 21. 5. Clostridia-directed enzyme prodrug therapy (CDEPT) *PCE = Prodrug Cleavage Enzyme
  22. 22. Thank You

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