Chapter B Prodrugs and Drug Delivery Systems 502 TABLE 8.1 Ester Analogs of Alcohols as Prodrugs Drug-OH--Drug-Ox X Effect on water solubility (R aliphatic or aromatic) C-R decreases C-CH2NHMe2 increases (pK,-8) CH-CH-COO- increases (pK -5) increases (pK.-4) PO3= increases (pK.-2 and -6) CCH2SO3 increases (pK,-1) Drug-OH+O0C 入C00 Scheme 8.2Intramolecular catalysis of succinate esters employed.Alcohol-containing drugs also can be converted into the corresponding acetals or ketals for rapid hydrolysis in the acidic medium of the gastrointestinal tract. Enolic hydroxyl groups can be esterified to prodrug forms as well.A series of enol esters of the antirheumatic oxindole 8.1 were prepared,and it was found that the hemifumarate derivative(82)was more stable than the corresponding nonionizable esters at neutralpH. HOOC OH H-N oxindole B.1 82
Seon 82 Mechanisms of Drug Activation 503 Carboxylic acid-containing drugs can be esterified with various alcohols.The reactivity ofthederivatized drugcan be adjusted by appropriate structural manipulationss discussed above for ester prodrugs of alcohol-containing drugs.The p of a carboxylic acid can be raised by conversion to a choline ester (8.3.R=R=Me:p7)or an amino ester (8.3. R=H.R=H or Me:pKa9).Likewise,phosphate-or phosphonate-containing drugs can be converted into ester prodrug forms,such as 3-phthalidylesters(84) 8.3 8.4 b.Amines N-Acylation of amines to give amide prodrugs is not commonly used,in general,because of the stability of amides toward metabolic hydrolysis.Activated amides.generally of low basicity amines,or amides of amino acids are more susceptible to enzymatic cleavage (Table 8.2). Although carbamates in general are too stable,phenyl carbamates(RNHCO2Ph)are rapidly cleaved by plasma enzymes and,therefore,they can be used as prodrugs. The pKa of amines can be lowered by approximately three units by conversion to their N-Mannich bases (Table 8.2.X=CH2NHCOAr).This lowers the basicity of the amine so that at physiological pH few of the prodrug molecules are protonated,thereby increasing its lipophilicity.For example,the partition coefficient (see Chapter 2.Sec- tion 2.2.F.2.b.p.55)between octanol and phosphate buffer,pH7.4for the N-Mannich base8.5 (R=CH2NHCOPh),derived from benzamide and the decongestant phenylpropanolamine hydrochloride(8.5.R=H.HCI:in several cold remedies,such as Entex).is almost 100 times greater than for the parent amine However,the rate of hydrolysis of N-Mannich bases depends on the amide carrier group:salicylamide and succinimide are more susceptible to hydrolysis than is benzamide.2 OH -CH NHR phenylpropanolamine hydrochloride(R =H-HCI) 8.5 TABLE 8.2 Prodrug Analogs of Amines Dug一NH 一·Dug-NHN X CHA NA
504 Chapter 8 Prodrugs and Drug Delivery Systems Another approach for lowering the pa of amines and,thereby,making them more lipophilic,is to convert them to imines(Schiff bases):however,imines often are too labile inaqueous solution.The anticonvulsant agent progabide (8.6:Gabrene)isa prodrug form of y-aminobutyric acid,an important inhibitory neurotransmitter (see Chapter 5. Section 5.5.C.3.a.p.287);once inside the brain it is hydrolyzed to y-aminobutyric acid. OH progabide 8.6 Because most solid tumors are hypoxic (have a low oxygen concentration),these cells are resistant toradiation therapy and to many chemotherapeutic approaches.15 To take advantage of the reductive milieu,prodrugs that require reductive mechanisms are beneficial.Although most carrier-linked prodrugs require hydrolytic activation mechanisms,a reductive activation mechanism also is feasible.A general approach is the reduction of a nitroaromatic prodrug (8.7,X =NH or O;Y =O,S,NCH3;Z =CH,N),converting the electron-withdrawing nitro group to an electron-donating hydroxylamino group(or amino group,depending on the rate of elimination versus the in vivo rate of reduction of the hydroxylamino to an amino group),which initiates release of the drug from the carrier.This can be used for release of amines(X =NH)or alcohols (X=O)from the carrier(Scheme 8.3).116]The drawback to this approach is that 8.8 is quite electrophilic and will react with whatever nucleophiles may be present,including other proteins,unless it is trapped possibly by the reducing agent or by glutathione (see Chapter 7,Section 7.4.C.5). c.Sulfonamides Just like amines,sulfonamides can be acylated,but this generates an acidic proton,which makes these compounds amenable to conversion to water-soluble sodium salts.For example, the second-generation anti-inflammatory drug and COX-2 inhibitor valdecoxib(8.9.Bextra) (see Chapter 5.Section 5.5.B.2.b,p.280)has been converted into parecoxib sodium(8.10. OH OH NO NH bioreduction Drug 8.7 8.8 Scheme 8.3Bioreductively activated carrier-linked prodrug
2 Mechanisms of Drug Activation Dynastat)an injectable analgesic drug The plasma half-lifein humans for 505 back to valdecoxib is about 5 minutes. P Na CH valdecoxib 8.9 parecoxib sodium 8.10 d.Carbonyl Compounds The most important prodrug forms of aldehydes and ketones are Schiff bases,oximes,acetals (ketals),enol esters,oxazolidines,and thiazolidines(Table 8.3). A more complete review of bioreversible derivatives of the functional groups was written by Bundgaard.18) A.2 Examples of Carrier-Linked Bipartate Prodrugs a. Prodrugs for Increased Water Solubility Prednisolone(8.11,R =R'=H;Prelone)and methylprednisolone(8.11.R=CH3.R'=H: Depo-Medrol)are poorly water-soluble corticosteroid drugs.To permit aqueous injection or opthalmic delivery of these drugs,they must be converted into water-soluble forms,such as one of the ionic esters described in Section 8.2.A.1.a.However.there are two considerations in the choice of a solubilizing group:The ester must be stable enough in aqueous solution so that a ready-to-inject solution has a reasonably long shelf life (greater than 2 years:half- life about 13 years).but it must be hydrolyzed invivo with a reasonably shor half-life after administration(less than 10 minutes).For this optimal situation to occur,theinnt TABLE 8.3 Prodrug Analogs of Carbonyl Compounds Dug、X Drug、 =0 R OR C=NR' C-NOH
506 Chapter 8 Prodrugs and Drug Delivery Systems ould have to be on the order of 100.This is possible when e is enzyme catalyzed. Me OH OR HO Me prednisolone(R R'=H) methylprednisolone(R CH3,R'=H) methylprednisolone sodium succinate(R=CH3,R'=COCH2CH2CO2Na) prednisolone phosphate(R=H,R'=PO3Na2) 8.11 The water-soluble prodrug form of methylprednisolone that is in medical use is methyl- prednisolone sodium succinate(8.11,R =CH3.R'=COCH2CH2CO2Na;Solu-Medrol). However,the in vitro stability is low,probably because of intramolecular catalysis;conse quently,it is distributed as a lyophilized(freeze-dried)powder that must be reconstituted with water and then used within 48 h.The lyophilization process adds to the cost of the drug and makes its use less convenient.On the basis of physical-organic chemical rationaliza- tions,a series of more stable water-soluble methylprednisolone esters was synthesized,and several of the analogs were shown to have shelf lives in solution of greater than 2 years at room temperature.19 Ester hydrolysis studies of these compounds in human and monkey serum indicated that derivatives having an anionic solubilizing moiety such as carboxylate or sulfonate are poorly or not hydrolyzed,but compounds with a cationic (tertiary amino)solu- bilizing moiety are hydrolyzed rapidly by serumesterases2 Prednisolone phosphate(811. R=H,R'=PO3Na2:Pediapred)is prescribed as a water-soluble prodrug for prednisolone that is activated in vivo by phosphatases. Because of the poor water solubility of the antitumor drug etoposide (8.12.R=H; Vepesid),it has to be formulated with the detergent Tween80.polyethylene glycol,and ethanol, all of which have been shown to be toxic.21 Conversion to the corresponding phosphate ester, etoposide phosphate(8.12.R=PO3H2:Etopophos),allows the drug to be delivered in a more concentrated form over a much shorter period of time without the detrimental vehicle22 HO CHO OCHs OR etoposide(R=H) etoposide phosphate(R=PO3H2) 8.12