上海交通大学：《药物化学》课程教学资源（书籍文献）Prodrugs and Drug Delivery Systems.pdf_大学文库

498 Chapter 8 Prodrugs and Drug Delivery Systems B.Bioprecursor Prodrugs 526 1.Origins. 2.Proton Activation:An Abbreviated Case History of the 526 Discovery of omeprazole. 527 3.Hydrolytic Activation................................................. 528 4.Elimination Activation................................................... 530 5.Oxidative Activation................................. 530 a.N-and O-Dealkylations................................ 530 b.Oxidative Deamination 530 c.N-Oxidation.............. 532 d.S-Oxidation................................................. 535 e.Aromatic Hydroxylation...................................... 536 1.Other Oxidations................ 536 6.Reductive Activation.................. 537 a.Azo Reduction........... 537 b.Azido Reduction 538 c.Sulfoxide Reduction........ 538 d.Disulfide Reduction....... 538 e.Nitro Reduction........... 539 7.Nucleotide Activation..... 540 8.Phosphorylation Activation 541 9.Sulfation Activation....... 543 10.Decarboxylation Activation 544 8.3 General References. 546 8.4 Problems.… 547 8.5 References................... .549 8.1 Enzyme Activation of Drugs The term prodrug,which was used initially by Albert,is a pharmacologically inactive compound that is converted into an active drug by a metabolic biotransformation.A prodrug also can be activated by a nonenzymatic process such as hydrolysis,but in this case the compounds generally are inherently unstable and may cause stability problems.The prodrug to drug conversion can occur before absorption,during absorption,after absorption,or at a specific site in the body.In the ideal case a prodrug is converted to the drug as soon as the desired goal for designing the prodrug has been achieved. As noted in Chapter 7.Section 7.4.D,p.471,the concepts of prodrugs and soft drugs (antedrugs)are opposite.Whereas prodrugs are inactive compounds that require a metabolic conversion to the active form,a soft drug is pharmacologically active and uses metabolism as a means of promoting excretion.However,it is possible to design a pro-sof drug a modified soft drug that requires metabolic activation for conversion to the active soft drug. 8.1.A Utility of Prodrugs Prodrug designisaled modification approach thatisusedtorreawinadrug candidate Below are numerousreasons why you might want to utilize a prodrug strategy in drug design

Section 8.1 Enzyme Activation of Drugs A.1 Aqueous Solubility 499 Consider an injectable drug that is so insoluble in water that it would need to be taken upn more than a liter of saline to administer the appropriate dose!Or what if each dose of your opthalmic drug required a liter of saline for dissolution,but it was to be administered as eye drops!These drugs could be safe,effective.and potent,but they would not be viable for their applications.In these cases,a water-solubilizing group couldbe attached to the drugwhich is metabolically released after drug administration. A.2 Absorption and Distribution If the desired drug is not absorbed and transported to the target site in sufficient concentration. it can be made more water soluble or lipid soluble depending on the desired site of action. Once absorption has occurred or when the drug is at the appropriate site of action,the water- or lipid-soluble group is removed enzymatically A.3 Site Specificity Specificity for a particular organ or tissue can be made if there are high concentrations of or uniqueness of enzymes present at that site that can cleave the appropriate appendages from the prodrug and unmask the drug.Alteratively,something that directs the drug to a particular type of tissue could be attached to the drug,which is released after the drug reaches the target tissue. A.4 Instability A drug may be rapidly metabolized and rendered inactive prior to when it reaches the site of action.The structure may be modified to block that metabolism until the drug is at the desired site. A.5 Prolonged Release It may be desirable to have a steady low concentration of a drug released over a long period of time.The drug may be altered so that it is metabolically converted to the active form slowly. A.6 Toxicity A drug may be toxic in its active form and would have a greater therapeutic index if it were administered in a nontoxic inactive form that was converted into the active form only at the site of action. A.7 Poor Patient Acceptability An active drug may have an unpleasant taste or odor,produce gastric irtation.oreause pain when administered(for example,when injected).The structure of the drug could be modified toalleviate these problems,but once administered.the prodrug would be metabolized tothe active drug

500 Chapter 8 Prodrugs and Drug Delivery Systems A.8 Formulation Problems If the drug is a volatile liquid,it would be more desirable to have it in a solid form so that it could be formulated as a tablet.An inactive solid derivative could be prepared that would be converted in the body to the active drug. 8.1.B Types of Prodrugs There are several classifications of prodrugs.Some prodrugs are not designed as such;the biotransformations are fortuitous.and it is discovered only after isolation and testing of the metabolites that activation of the drug had occurred.In most cases a specific modification in a drug has been made on the basis of known metabolic transformations.It is expected that after administration,the prodrug will be appropriately metabolized to the active form. This has been termed drug latentiation to signify the rational design approach rather than serendipiry.2 The term drug latentiation has been refined even further by Wermuth31 into two classes which he called carrier-linked prodrugs and bioprecursors. A carrier-linked prodrug is a compound that contains an active drug linked to a carrier group that can be removed enzymatically,such as an ester which is hydrolyzed to an active carboxylic acid-containing drug.The bond to the carrier group must be labile enough to allow the active drug to be released efficiently in vivo,and the carrier group must be nontoxic and biologically inactive when detached from the drug.Carrier-linked prodrugs can be subdivided even further into bipartate,tripartate,and mutual prodrugs.A bipartare prodrug is a prodrug comprised ofone carrier attached to the drug.When acarrier is connected to a linker that is con- nected to the drug,it is called a tripartate prodrug.A mutual prodrug consists of two,usually synergistic,drugs attached to each other(one drug is the carrier for the other and vice versa). A bioprecursor prodrug is a compound that is metabolized by molecular modification into a new compound which is the active principle or which can be metabolized further to the active drug.For example,if the drug contains a carboxylic acid group,the bioprecursor may be a primary amine that is metabolized by oxidation to the aldehyde,which is further metabolized to the carboxylic acid drug(see Chapter 7,Section 7.4.B.1.e,p.430).Unlike the carrier-linked prodrug.which is the active drug linked to a carrier,a bioprecursor prodrug contains a different structure that cannot be converted into the active drug by simple cleavage of a group from the prodrug. The concept of prodrugs can be analogized to the use of protecting groups in organic synthesis.141 If,for example,you wanted to carry out a reaction on a compound that contained acarboxylic acid group,it may be necessary first to protect the carboxylic acid as,say,an ester. so that the acidic proton of the carboxylic acid does not interfere with the desired reaction. After the desired synthetic transformation was completed,the carboxylic acid analog could be unmasked by deprotection,i.e.hydrolysis of the ester(Scheme 8.1A).This is analogous to a carrier-linked prodrug:an ester functionality can be used to make the properties of the drug more desirable until it reaches the appropriate biological site where itisdeprotected."Another type of protecting group in organic synthesis is one that has no resemblance to the desired funcgroupForexampeterminal alkene can be oxidized withoone toanaldehydes and the aldehyde can beoxidizedtacaboxylicacid with hydrogen peroxide(Scheme.1B). As inthe casof a bioprecursor prodrug a drastic structural change is required to unmask the desired group.Oxidation isacommon metabolic biotransformation for bioprecursor prodrugs. When designing prodrug you should keep in mind that a particular metabolic transfor mation may be species specific(seeChapter 7).Therefore,a prodrug whose design was based on rat metabolism studies may not necessarily be effective in humans

Section 8.2 Mechanisms of Drug Activation RCOH EIOH 501 H -RCO日 reaction R'CO,Er on R 、H0 4 -R'CO H B RCH=Ch,cm→R'CHCH on R 10 2H01 R'COH Scheme 8.1 Protecting group analogy for a prodrug 8.2 Mechanisms of Drug Activation 8.2.A Carrier-Linked Prodrugs An ideal drug carrier must(1)protect the drug until it is at the site of action:(2)localize the drug at the site of action:(3)allow for release of the drug chemically or enzymatically. (4)minimize host toxicity:(5)be biodegradable,biochemically inert,and nonimmunogenic; (6)be easily prepared inexpensively:and(7)be chemically and biochemically stable in its dosage form. The most common reaction for activation of carrier-linked prodrugs is hydrolysis.First. let's consider the general functional groups involved,then look at specific examples for different types of prodrugs. A.1 Carrier Linkages for Various Functional Groups a.Alcohols,Carboxylic Acids,and Related Groups There are several reasons why the most common prodrug form for drugs containing alcohol or carboxylic acid functional groups is an ester.First,esterases are ubiquitous.so metabolic regeneration of the drug is a facile process.Also,it is possible to prepare ester derivatives with virtually any degree of hydrophilicity or lipophilicity.Finally,a variety of stabilities of esters can be obtained by appropriate manipulation of electronic and steric factors.Therefore, a multitude of ester prodrugs can be prepared to accommodate a wide variety of problems that require the prodrug approach. Alcohol-containing drugs can be acylated with aliphatic or aromatie carboxylic acids to decrease water solubility(increase lipophilicity)or with carboxylic acids containing aminoor additional carboxylate groups to increase water solubility (Table 8.1)Conversion tophos- phate or sulfate esters also increases water solubility.By using these approaches a wide range of solubilities can be achieved that will affect the absorption and distribution properties of the drug.These derivatives also can have an important effect on the dosage form,that is,whether used in tablet form or in aqueous solution.One problem with the use of this prodrug approach is that in some cases certain esters are not very good substrates for the endogenous esterases sulfatases,or phosphatases,and may not be hydrolyzed at a rapid enough rate.When that occurs,however.a different ester can be tried.Another approach to accelerate the hydrolysis rate could be to attach electron-withdrawing groups (if a base hydrolysis mechanism is rel evant)or electron-donating groups (if an acid hydrolysis mechanism is important)to the carboxylate side of the ester.Succinate esters can be used to accelerate the rate of hydroly- sis by intramolecular catalysis(Scheme 8.2).If the ester is too reactive.substituents can be appended that cause steric hindrance to hydrolysis or esters of long-chain fatty acids can be

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