CHEMISTRY OF PRODRUGS 33 APPLICATIONS OF PRODRUGS Prodrugs are converted into the active drug within the body through enzymaticor non-enzymatic reactions.The various applications of prodrug approach are; 1.Improved physicochemical properties(e.g.,better solubility in the intended formula- tion) 2.Enhanced delivery characteristics and/or therapeutic value of the drug 3.To improve drug penetration through biological membranes 4 To in 6.To increase duration of pharmacological activity 7.To decrease the drug's toxicity and adverse effects 8.To improve patient acceptence. IDEAL REQUIREMENTS OF PRODRUGS 1.The pro rug is inactive or less activ e than the parent compound 2.The linkage between the drug and the carrier must be cleaved in vivo 3.The carrier molecule released in vivo must be non-toxic 4.The metabolic fragments of carrier molecule,apart from the drug should be non-toxic CLASSIFICATION OF PRODRUGS The prodrugs are classified according to the functional group.They are; 1.Carboxylic acids and alcohols.Prodrugs of carboxylic acid and alcohol functionalities can be prepared by conversion to an ester.The ester can be easily hydrolysed by esterase enzymes (ester hydrolase,lipase,cholesterol esterase,acetylcholinesterase, carboxypeptidase)present in plasma and other tissues to give active drug. Ex: OH H OH H CH- NH-C -CHCI, CH- -C-NHCOCHCL ○ CH,-0-C (CH)CH→ +CH (CH)-C-OH No. No, Chloramphenicol palmitate Chloramphenicol Palmitie acid Antibiotic prodrugs comprise the largest group of prodrugs developed to improve oral absorption
CHEMISTRY OF PRODRUGS 33 C-8—N-CHEMI\CHE4-1.PM5 Prodrugs are converted into the active drug within the body through enzymatic or non-enzymatic reactions. The various applications of prodrug approach are; 1. Improved physicochemical properties (e.g., better solubility in the intended formulation) 2. Enhanced delivery characteristics and/or therapeutic value of the drug 3. To improve drug penetration through biological membranes 4. To increase site specificity of the drug 5. To improve the drug’s stability and solubility 6. To increase duration of pharmacological activity 7. To decrease the drug’s toxicity and adverse effects 8. To improve patient acceptence. An ideal prodrug must meet the following requirements; 1. The prodrug is inactive or less active than the parent compound 2. The linkage between the drug and the carrier must be cleaved in vivo 3. The carrier molecule released in vivo must be non-toxic 4. The metabolic fragments of carrier molecule, apart from the drug should be non-toxic The prodrugs are classified according to the functional group. They are; 1. Carboxylic acids and alcohols. Prodrugs of carboxylic acid and alcohol functionalities can be prepared by conversion to an ester. The ester can be easily hydrolysed by esterase enzymes (ester hydrolase, lipase, cholesterol esterase, acetylcholinesterase, carboxypeptidase) present in plasma and other tissues to give active drug. Ex: OH CH——C—NH—C—CHCl2 Chloramphenicol palmitate H O O CH —O—C—(CH ) CH 2 2 14 3 NO2 OH CH——C—NHCOCHCl2 + CH (CH ) —C—OH 3 2 14 Chloramphenicol H O CH OH 2 NO2 Palmitic acid Antibiotic prodrugs comprise the largest group of prodrugs developed to improve oral absorption.
34 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY Ex:Pivampicillin,talampicillin and bacampicillin are prodrugs of ampicillin,all result- ing from the esterification of the polar carboxylate group.The absorption of these prodrugs is nearly complete (98-99%)whereas that of ampicillin is<50%. Enalapril,the most widely prescribed ACE inhibitor,is the ethyl ester prodrug of the active diacid,enalaprilat.Enalaprilat is poorly absorbed from the gastrointestinal tract ( 10%),but absorption of the prodrug enalapril is greatly improved (60%). 2.Amines.Due to high chemical stability of amide linkage and lack of amidase en- zymes amines are not derivatised to amide prodrugs.A more common approach has been to utilize mannich bases as a prodrug form of the amines. CHH,C、 CH,+0 COOH HC Ampicillin Acetone CH, -CH, CH, COOH Hetacillin 3.Azo Linkage.Amines are derivatised to azolinkage prodrugs Ex:Prontosil H.NN=NSO.NH,H.N SO NH NH Sulfanilamide Prontosil +HN-○》-NH NH2 4.Carbonyl compounds.Carbonyl functionalities such as aldehydes and ketones are converted to prodrugs.Ho ver this approach has not found wide clinical utility These have nerally involved derivatives in which the sp2 hybridized carbor nvl carbon is erted to ar attached to two hete h itrogen,or sulfur.These ar reconverted to the mpounds Ex:Methenamine releases HCHO in the urine,which acts as an antibacterial agent
34 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY C-8—N-CHEMI\CHE4-1.PM5 Ex: Pivampicillin, talampicillin and bacampicillin are prodrugs of ampicillin, all resulting from the esterification of the polar carboxylate group. The absorption of these prodrugs is nearly complete (98-99%) whereas that of ampicillin is < 50%. Enalapril, the most widely prescribed ACE inhibitor, is the ethyl ester prodrug of the active diacid, enalaprilat. Enalaprilat is poorly absorbed from the gastrointestinal tract (< 10%), but absorption of the prodrug enalapril is greatly improved (60%). 2. Amines. Due to high chemical stability of amide linkage and lack of amidase enzymes amines are not derivatised to amide prodrugs. A more common approach has been to utilize mannich bases as a prodrug form of the amines. NH2 CH3 CH3 COOH + O=C H C3 H C3 NH O S N O Ampicillin Acetone HN CH3 CH3 O N S O CH3 CH3 COOH N Hetacillin 3. Azo Linkage. Amines are derivatised to azolinkage prodrugs. Ex: Prontosil H N—2 H N—2 H N—2 —N = N— —SO NH 2 2 —SO NH 2 2 —NH2 NH2 Azoreductase NH2 + Prontosil Sulfanilamide 4. Carbonyl compounds. Carbonyl functionalities such as aldehydes and ketones are converted to prodrugs. However this approach has not found wide clinical utility. These have generally involved derivatives in which the sp2 hybridized carbonyl carbon is converted to an sp3 hybridised carbon attached to two heteroatoms such as oxygen, nitrogen, or sulfur. These prodrugs are reconverted to the carbonyl compounds by hydrolysis. Ex: Methenamine releases HCHO in the urine, which acts as an antibacterial agent
CHEMISTRY OF PRODRUGS 35 N H, CH H 6HCHO Formaldehyde Methenamine DEVELOPMENT OF PRODRUGS: 1.To Improve patient acceptance.One of the reasons for poor patient compliance, particularly in case of children,is the bitterness,acidity or causticity of the drug.Two ap- proaches can be utilized to overcome the bad taste of drug.The first is reduction of drug solu- bility in saliva and the other is to lowers the affinity of drug towards taste receptors. Clndmy ha bittrstesitis not acep idren.I w fund acylesters of cli lamycin, the taste improved from ate ester CHa CH. CH, CH H C.H. -NH一 C.H. NH HO个 HO HO Phosphatase SCH, SCH O=P-OH 0 duce giittionerdrgAnicin diethylstilboestrol)cause irritation and damage to gas tric muc osa.These an beo e by changing to prod Ex.Salicylic acid to aspirin COOH
CHEMISTRY OF PRODRUGS 35 C-8—N-CHEMI\CHE4-1.PM5 N N CH2 CH2 H2 N C N Methenamine H+ 6HCHO + 4NH3 Formaldehyde Ammonia The successes of prodrug design are many, and a large variety of such compounds have proven their therapeutic value. Some important prodrug concepts are described below; 1. To Improve patient acceptance. One of the reasons for poor patient compliance, particularly in case of children, is the bitterness, acidity or causticity of the drug. Two approaches can be utilized to overcome the bad taste of drug. The first is reduction of drug solubility in saliva and the other is to lowers the affinity of drug towards taste receptors. Ex. : Clindamycin has bitter taste, so it is not well accepted by children. It was found that by increasing the chain-length of 2-acylesters of clindamycin, the taste improved from bitter to non-bitter taste (phosphate ester). N CH3 C H3 8 C———NH O CH3 SCH3 CH3 + H H Cl H O O O– O = P—OH HO HO Clindamycin phosphate Phosphatase N CH3 C H3 8 C———NH O CH3 SCH3 + H PO 3 4 CH3 + H H Cl H O HO HO HO Clindamycin 2. To reduce gastric irritation. Several drugs (NSAIDS, nicotinic acid, kanamycin, diethylstilboestrol) cause irritation and damage to gastric mucosa. These problems of drugs can be overcome by changing to prodrugs. Ex. : Salicylic acid to aspirin
36 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY Nicotinic acid to nicotinic acid hydrazide COOH -NHNH, 8.To im ve chemical stability.Several drugs ose during their shelf improve stability. Ex.:Aza atineoplastic drug)in aqueous solution is readily hydrolyzed but it NH, H Bisulphite pr 4.Prodrugs for increased water solubility.Drugs with hydroxyl functional group can be converted into their hydrophilic forms by use of half-esters such as hemiglutarates or hemiphthalates;the other half of these acidic carriers can form sodium,potassium or amine salts and render the moiety water soluble. Prednisolone phosphate is a water phosphatases. CH2OH CH.O-PO,Na =0 H.C OH .OH Prednisolone Predn 5.To decrease drug's toxicity and adverse effects.An important objective of drug design is to develop drugs with high activity and low toxicity
36 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY C-8—N-CHEMI\CHE4-1.PM5 Nicotinic acid to nicotinic acid hydrazide COOH N C—NHNH2 N O 3. To improve chemical stability. Several drugs may decompose during their shelf life or in the GIT when used orally. The prodrug approach of such drugs is a good technique to improve stability. Ex. : Azacytidine (antineoplastic drug) in aqueous solution is readily hydrolyzed but its bisulphite prodrug is stable. NH2 NH2 SO H3 H N N O O N N N N Ribose Azacytidine Ribose Bisulphite prodrug of azacytidine 4. Prodrugs for increased water solubility. Drugs with hydroxyl functional group can be converted into their hydrophilic forms by use of half-esters such as hemiglutarates or hemiphthalates ; the other half of these acidic carriers can form sodium, potassium or amine salts and render the moiety water soluble. Ex. : Prednisolone and methylprednisolone are poorly water-soluble corticosteroid drugs. Prednisolone phosphate is a water-soluble prodrug of prednisolone that is activated in vivo by phosphatases. O H C3 H C3 CH OH 2 C O C O OH H H HO Prednisolone O H C3 H C3 CH O–PO Na 2 3 – + H H OH OH Prednisolone sodium phosphate 5. To decrease drug’s toxicity and adverse effects. An important objective of drug design is to develop drugs with high activity and low toxicity
CHEMISTRY OF PRODRUGS Ex.:Dipivaloylepinephrine prodrug instead of epinephrine to treat glaucoma OH H H -CH-N-CH H-C-CH/-NH-CH3 CH, -CH, OH OH CH O CH H,C- C=0 Epinephrine CH Esterification of aspirin greatly suppresses gastric uterogenic activity. COOH COOR 0-CH Aspirin Ester form of Aspirir 6.To impr ort.Barbiturates are a group of comp ds respo sible for nd h ect.The and ar erted to the onding sodium salt in sodium salt is ber of this groun ofcomnounds various barbiturates differ in the time required for the onset of sleep and in the duration of their effect.Hexobarbitone was found to be an effective drug but its membrane permeability was found to be low.However N-methylhexobarbitone a simple de- rivative of the parent drug was found to have better permeability characteristics.After intake, the N-methyl group is cleaved in the liver to release the physiologically active drug. Hexobarbitone N-Methylhexobarbitone Similarly,membrane transportation characteristics of the neurotransmitter dopamine used for the treatment of Parkinson's di se can be improved by administering its prodrug L 3,4-dihydroxyphenylalanine (Levo-DOPA) This derivative has better blood-brain permeatior no acid channels for transportation.Once inside the cell the acid group to generate dopamine
CHEMISTRY OF PRODRUGS 37 C-8—N-CHEMI\CHE4-1.PM5 Ex. : Dipivaloylepinephrine prodrug instead of epinephrine to treat glaucoma. H—C—CH —N—CH 2 3 OH H OH OH Epinephrine Dipivaloyl epinephrine H—C—CH —NH—CH 2 3 OH O—C—C—CH3 H C—C——C = O 3 O CH3 CH3 CH3 CH3 O Esterification of aspirin greatly suppresses gastric uterogenic activity. 6. To improve membrane transport. Barbiturates are a group of compounds responsible for profound sedative and hypnotic effect. They are weakly acidic in nature and are converted to the corresponding sodium salt in aqueous sodium hydroxide. The sodium salt is extensively employed for intravenous anesthetic properties. Barbituric acid is the parent member of this group of compounds. Various barbiturates differ in the time required for the onset of sleep and in the duration of their effect.Hexobarbitone was found to be an effective drug but its membrane permeability was found to be low. However N-methylhexobarbitone a simple derivative of the parent drug was found to have better permeability characteristics. After intake, the N-methyl group is cleaved in the liver to release the physiologically active drug. O O O Barbituric acid N H NH O O O Hexobarbitone N H NCH3 H C3 H C3 O O O N-Methylhexobarbitone N CH3 NCH3 Similarly, membrane transportation characteristics of the neurotransmitter dopamine used for the treatment of Parkinson’s disease can be improved by administering its prodrug L- 3,4-dihydroxyphenylalanine (Levo-DOPA). This derivative has better blood-brain permeation characteristics since it uses amino acid channels for transportation. Once inside the cell, decarboxylase enzyme removes the acid group to generate dopamine