The Organic Chemistry of
`Drug Design and Drug Action
`
`Richard B. Silverman
`Department of Chemistry
`Northwestern University
`Evanston, Illinois
`
`ACADEMIC PRESS
`A Division of Harcourt Brace & Company
`San Diego New York Boston London Sydney Tokyo Toronto
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`This book is printed on acid-free paper. (D
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`Copyright © 1992 by ACADEMIC PRESS
`All Rights Reserved.
`No part of this publication may be reproduced or transmitted in any form or by any
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`Academic Press
`A Division of Harcourt Brace & Company
`525 B Street, Suite 1900, San Diego, California 92101-4495
`United Kingdom Edition published by
`Academic Press Limited
`24-28 Oval Road, London IsIV/1 7DX
`
`Library of Congress Cataloging-in-Publication Data
`
`Silverman, Richard B.
`The organic chemistry of drug design and drug action / Richard B.
`Silverman.
`p. cm.
`Includes index.
`ISBN 0-12-643730-0 (hardcover)
`1. Pharmaceutical chemistry. 2. Bioorganic chemistry.
`3. Molecular pharmacology. 4. Drugs--Design. I. Title.
`[DNLM: 1. Chemistry, Organic. 2. Chemistry, Pharmaceutical.
`3. Drug Design. 4. Pharmacokinetics. QV 744 S587o]
`RS403.S55 1992
`615'.19—dc20
`DNLM/DLC
`for Library of Congress (cid:9)
`
`Printed in the United States of America
`98 99 MM 8 7 6
`
`91-47041
`CIP
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`
`CHAPTER 8
`
`Prodrugs and Drug Delivery Systems
`
`Ir
`
`352
`
`I. Enzyme Activation of Drugs (cid:9)
`352
`A. Utility of Prodrugs (cid:9)
`1. Solubility, 353 • 2. Absorption and Distribution, 353 • 3. Site Specificity, 353 •
`4. Instability, 353 • 5. Prolonged Release, 353 • 6. Toxicity, 353 • 7. Poor Patient
`Acceptability, 353 • 8. Formulation Problems, 354
`354
`B. Types of Prodrugs (cid:9)
`II. Mechanisms of Prodrug Activation (cid:9)
`355
`A. Carrier-Linked Prodrugs (cid:9)
`1. Carrier Linkages for Various Functional Groups, 355 • 2. Examples of
`Carrier-Linked Bipartate Prodrugs, 358 • 3. Macromolecular Drug Carrier Systems,
`368 • 4. Tripartate Prodrugs, 374 • 5. Mutual Prodrugs, 376
`377
`B. Bioprecursor Prodrugs (cid:9)
`1. Origins, 377 • 2. Oxidative Activation, 378 • 3. Reductive Activation, 385 •
`4. Nucleotide Activation, 391 • 5. Phosphorylation Activation, 392 •
`6. Decarboxylation Activation, 394
`
`355
`
`References 397
`General References (cid:9)
`
`401
`
`I. Enzyme Activation of Drugs
`
`The term prodrug, which was used initially by Albert,' refers to a pharmaco-
`logically inactive compound that is converted to an active drug by a metabolic
`biotransformation. A prodrug also can be activated by a nonenzymatic pro-
`cess such as hydrolysis, but in this case the compounds usually are inherently
`unstable and may cause stability problems. The prodrug-to-drug conversion
`can occur before absorption, during absorption, after absorption, or at a spe-
`cific 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. It
`should be noted that although the compounds discussed in this chapter are
`illustrative of the approaches taken for the design of prodrugs, many of them
`have not been approved for medical use.
`
`A. Utility of Prodrugs
`
`There are numerous reasons why one may wish to utilize a prodrug strategy in
`drug design. Specific examples of each of these categories are given in Section
`II,A,2.
`
`352
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`I. Enzyme Activation of Drugs (cid:9)
`
`1. Solubility
`
`353
`
`Consider an active drug that is insufficiently soluble in water so that it cannot
`be injected in a small dose. A water-soluble group could be attached which
`could be metabolically released after drug administration.
`
`2. Absorption and Distribution
`
`If the 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 re-
`moved enzymatically.
`
`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 which can
`cleave the appropriate appendages from the prodrug and unmask the drug.
`
`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 metab-
`olism until the drug is at the desired site.
`
`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.
`
`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
`to the active form only at the site of action.
`
`7. Poor Patient Acceptability
`
`An active drug may have an unpleasant taste or odor, produce gastric irrita-
`tion, or cause pain when administered (e.g., when injected). The structure of
`the drug can be modified to alleviate these problems, but once administered,
`the altered drug can be metabolized to the active drug.
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`354 (cid:9)
`
`8. Prodrugs and Drug Delivery Systems
`
`8. Formulation Problems
`If the drug is a volatile liquid, it would be more desirable to prepare it in a solid
`form so that it could be formulated as a tablet. An inactive solid derivative
`could be prepared which would be converted in the body to the active drug.
`
`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 after isola-
`tion 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 it
`will be appropriately metabolized to the active form. This has been termed
`drug latentiation to signify the rational design approach rather than serendip-
`ity .2 The term drug latentiation has been refined even further 6y Wermuth3
`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 subdi-
`vided even further into bipartate, tripartate, and mutual prodrugs. A bipartate
`prodrug is a prodrug comprised of one carrier attached to the drug. When a
`carrier is connected to a linker arm which is connected to the drug, the term
`tripartate prodrug is used. A mutual prodrug consists of two, usually syner-
`gistic, drugs attached to each other (one drug is the carrier for the other and
`vice versa)'.
`A bioprecursor is a compound that is metabolized by molecular modifica-
`tion 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 which is
`metabolized by oxidation to the aldehyde which is further metabolized to the
`carboxylic acid drug (see Section IV,B,I,e of Chapter 7). Unlike a carrier-
`linked prodrug, which is the active drug linked to a carrier that generally is
`released by a hydrolytic reaction, a bioprecursor contains a different structure
`that cannot be converted to tht 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.4 If, for example, you wanted to carry out a reaction on a
`compound that contained a carboxylic acid group, it may be necessary first to
`protect the carboxylic acid as, say, an ester, so that the acidic proton of the
`
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`II. Mechanisms of Prodrug Activation (cid:9)
`
`355
`
`carboxylic acid does not interfere with the desired reaction. After the desired
`synthetic transformation is completed, the carboxylic acid analog could be
`unmasked by deprotection, that is, hydrolysis of the ester (Scheme 8.1A).
`This is analogous to a carrier-linked prodrug; an ester functionality can be
`used to give the drug more desirable properties until it reaches the appropriate
`biological site where it is "deprotected." Another type of protecting group in
`organic synthesis is one which has no resemblance to the desired functional
`group. For example, a terminal alkene can be oxidized with ozone to an
`aldehyde,5 and the aldehyde can be oxidized to a carboxylic acid with hydro-
`gen peroxide (Scheme 8.1B). As in the case of a bioprecursor, a drastic
`structural change is required to unmask the desired group. Oxidation is a
`common metabolic biotransformation for bioprecursors.
`
`A. RCO2H
`
`EtOH
`HC1
`A
`
`•
`
`RCO2Et
`
`reaction
`on R
`
`R'CO2Et
`
`H30+
`
`A
`
`(cid:9) • (cid:9) R'CO2H
`
`B. (cid:9)
`
`reaction
`RCH=CH2 rea R
`on
`
`R'CH=CH2
`
`1. 03 .0..
`2. H202
`
`R'CO2H
`
`Scheme 8.1. Protecting group analogy for a prodrug.
`
`When designing a prodrug, you should keep in mind that a particular meta-
`bolic transformation may be species specific (see Chapter 7). Therefore, a
`prodrug designed on the basis of rat metabolism studies may not necessarily
`be effective in humans.
`
`II. Mechanisms of Prodrug Activation
`A. Carrier-Linked Prodrugs
`
`The most common reaction for activation of carrier-linked prodrugs is hydro-
`lysis. First, we consider the general functional groups involved, then specific
`examples for different types of prodrugs will be given.
`
`1. Carrier Linkages for Various Functional Groups
`
`a. Alcohols and Carboxylic Acids. 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. Fi-
`nally, a variety of stabilities of esters can be obtained by appropriate manipu-
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`1
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`356 (cid:9)
`
`8. Prodrugs and Drug Delivery Systems
`
`lation 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 aromatic carbox-
`ylic acids to decrease water solubility (increase lipophilicity) or with carbox-
`ylic acids containing amino or additional carboxylate groups to increase water
`solubility (Table 8.1).6 Conversion to phosphate or sulfate esters also in-
`creases water solubility. By using these approaches a wide range of solubili-
`ties 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 the esters are not
`very good substrates for the endogenous esterases, sulfatases, or phospha-
`tases , and they may not be hydrolyzed at a rapid enough rate. When that
`occurs, however, a different ester can be tried. Another approach to acceler-
`ate the hydrolysis rate could be to attach electron-withdrawing groups (if a
`
`Table 8.1 Ester Analogs of Alcohols as Prodrugs
`
`Drug—OH (cid:9)
`
`> Drug—OX
`
`X (cid:9)
`
`0
`C—R
`
`0
`
`C — CH2NMe2
`
`H
`
`0
`c — cH2cH2c00- (cid:9)
`
`\= NH
`
`P03 = (cid:9)
`
`0
`Iccii2s0 (cid:9)
`
`Effect on water solubility
`
`(R = aliphatic or aromatic)
`decreases
`
`increases (pKa — 8)
`
`increases (pKa — 5)
`
`increases (pKa — 4)
`
`increases (pKa — 2 and — 6)
`
`increases (pKa — 1)
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`II. Mechanisms of Prodrug Activation (cid:9)
`
`357
`
`base hydrolysis mechanism is relevant) or electron-donating groups (if an acid
`hydrolysis mechanism is important)7 to the carboxylate side of the ester.
`Succinate esters can be used to accelerate the rate of hydrolysis by intramo-
`lecular catalysis (Scheme 8.2). If the ester is too reactive, substituents can be
`appended that cause steric hindrance to hydrolysis. Alcohol-containing drugs
`also can be converted to the corresponding acetals or ketals for rapid hydroly-
`sis in the acidic medium of the gastrointestinal tract.
`
`0
`
`I
`
`
`
`1.- Drug 0- (cid:9)
`
`0
`
`Drug OH + -00CCOO"
`
`Drug — 0 • -
`
`0
`
`Scheme 8.2.
`
`Intramolecular hydrolysis of succinate esters.
`
`Carboxylic acid-containing drugs also can be esterified; the reactivity of the
`derivatized drug can be adjusted by appropriate structural manipulations. If a
`slower rate of ester hydrolysis is desired, long-chain aliphatic or sterically
`hindered esters can be used. If hydrolysis is too slow, addition of electron-
`withdrawing groups on the alcohol part of the ester can increase the rate. The
`pKa of a carboxylic acid can be raised by conversion to a choline ester (8.1,
`R = R' = Me; pKa — 7) or an amino ester (8.1, R = H, R' = H or Me;
`pKa — 9).
`
`O
`
`Drug—C-0—CH2CH2—NRR'2
`
`8.1
`b. Amines. N-Acylation of amines to give amide prodrugs is not com-
`monly 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
`
`Table 8.2 Prodrug Analogs of Amines
`
`Drug—NH2 ----> Drug—NHX
`
`X
`
`o (cid:9)
`0
`0 (cid:9)
`O (cid:9)
`II
`II (cid:9)
`+ (cid:9)
`II (cid:9)
`II (cid:9)
`—CR —CCHNH3 —C—OPh —CH2NHCAr =CHAr
`I
`R
`
`=NAr
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`358 (cid:9)
`
`8. Prodrugs and Drug Delivery Systems
`
`1
`
`carbamates in general are too stable, phenyl carbamates (RNHCO2Ph) are
`rapidly cleaved by plasma enzymes,8 and, therefore, they can be used as
`prodrugs.
`The pKa values of amines can be lowered by approximately 3 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, Section 1I,E,2,b) between octanol and
`phosphate buffer, pH 7.4, for the N-Mannich base derived from benzamide
`(8.2, R = CH2NHCOPh) and the decongestant phenylpropanolamine (8.2,
`R = H) is almost 100 times greater than that for the parent amine.9 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.1°
`Another approach for lowering the pK, values of amines and, thereby,
`making them more lipophilic, is to convert them to imines (Schiff bases);
`however, imines often are too labile in aqueous solution. The anticonvulsant
`agent progabide (8.3) is a prodrug form of y-aminobutyric acid, an important
`inhibitory neurotransmitter (see Chapter 5, Section V,C,3,a). The lipophilic-
`ity of 8.3 allows the compound to cross the blood—brain barrier; once inside
`the brain it is hydrolyzed to y-aminobutyric acid."
`
`NHR
`8.2
`
`C'
`8.3
`
`c. Carbonyl Compounds. The most important prodrug forms of aldehydes
`and ketones are Schiff bases, oximes, acetals (ketals), enol esters, oxazoli-
`dines, and thiazolidines (Table 8.3). A more complete review of bioreversible
`derivatives of the functional groups was written by Bundgaard.6
`
`2. Examples of Carrier-Linked Bipartate Prodrugs
`
`a. Prodrugs for Increased Water Solubility. Prednisolone (8.4; R =
`R' = H) and methylprednisolone (8.4; R = CH3, R' = H) are poorly water-
`soluble corticosteroid drugs. In order to permit aqueous injection or ophthal-
`mic delivery of these drugs, they must be converted to water-soluble forms
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`
`II. Mechanisms of Prod rug Activation (cid:9)
`
`359
`
`Table 8.3 Prodrug Analogs of Carbonyl Compounds
`Drug (cid:9)
`Drug x
`\/
`\ (cid:9)
`C=0 (cid:9)
`i \
`R Y
`R (cid:9)
`
`-
`
`/
`
`C
`
`X
`
`Y
`
`X
`C
`Y
`
`= (cid:9)
`
`C=NR' (cid:9)
`
`/OR' (cid:9)
`C=NOH C (cid:9)
`\ (cid:9)
`OR' (cid:9)
`
`/O-1 (cid:9)
`C, ) (cid:9)
`N (cid:9)
`H (cid:9)
`
`s
`d,
`N
`H
`
`such as one of the ionic esters described in Section II,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 in vivo with a reasonably short half-life after administra-
`tion (less than 10 min). For this optimal situation to occur the in vivolin vitro
`lability ratio would have to be on the order of 106. This is possible when the
`biotransformation is enzyme catalyzed.
`The water-soluble prodrug form of methylprednisolone that is in medical
`use is methylprednisolone sodium succinate (8.4, R = CH3, R' = COCH2-
`CH2CO2Na). However, the in vitro stability is low; consequently, it is distrib-
`uted as a lyophilized (freeze-dried) powder that must be reconstituted with
`water and then used within 48 hr. The lyophilization process adds to the cost
`of the drug and makes its use less convenient. On the basis of physical-
`organic chemical rationalizations, 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 tempera-
`ture.'2 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
`
`OH OR'
`Me
`
`HO
`M
`
`1.1
`8.4
`
`.1
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`
`360 (cid:9)
`
`8. Prodrugs and Drug Delivery Systems
`
`cationic (tertiary amino) solubilizing moiety are hydrolyzed rapidly by serum
`esterases.13 Prednisolone phosphate (8.4; R = H, R' = PO3Na2) is prescribed
`as a water-soluble prodrug for prednisolone that is activated in vivo by phos-
`phatases.
`The local anesthetic benzocaine (8.5, R = H) has been converted to water-
`soluble amide prodrug forms with various amino acids (8.5, R = NH3-
`CHR'CO); amidase-catalyzed hydrolysis in human serum occurs rapidly."
`
`RNH
`
`CO2Et
`
`8.5
`Another prodrug approach is to design acyclic derivatives that are enzymat-
`ically hydrolyzed to a product that spontaneously cyclizes to the desired drug.
`The benzodiazepine tranquilizer diazepam (8.8, Scheme 8.3) is very sparingly
`water soluble, but the open chain amino ketone coupled to an amino acid or
`peptide is a stable, freely water-soluble prodrug (8.6); in vivo peptidases hy-
`drolyze the peptide bond, and the resulting 2-aminoacetamidobenzophenone
`analog (8.7) spontaneously cyclizes to give the benzodiazepine.'5,16 The rate
`of in vivo hydrolysis of the peptide bond depends on which L-amino acid is
`attached; peptides derived from Phe and Lys are cleaved much faster than
`those from Gly and Glu. The rate of cyclization depends on the substituents in
`the phenyl ring and on the amide nitrogen. Although the cyclization of 8.7 to
`8.8 occurs with a half-life of 73 sec, that for the corresponding N-desmethyl
`analog is 15 min. As an example of how effective this approach is for increas-
`ing the water solubility, the benzodiazepine triazolam (8.9, R = Cl) has a
`solubility of 0.015 mg/ml at 25° C, but the corresponding open-chain glycyl-
`aminobenzophenone derivative (HC1 salt) has a solubility of 109 mg/ml.'7 A
`similar prodrug approach was taken for the benzodiazepine alprazolam (8.9,
`R = H).'8
`
`R
`
`-00C NH3
`
`R
`
`amidase
`
`CI
`
`NH3+ (cid:9)
`
`CI
`
`CI
`
`8.6
`
`8.7
`
`8.8
`
`Scheme 8.3. Benzodiazepine prodrug activation.
`
`b. Prodrugs for Improved Absorption and Distribution. The skin is de-
`signed to maintain the body fluids and prevent absorption of xenobiotics into
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`
`II. Mechanisms of Prodrug Activation (cid:9)
`
`361
`
`the general circulation. Consequently, drugs applied to the skin are poorly
`absorbed.19 Even steroids have low dermal permeability, particularly if they
`contain hydroxyl groups which can interact with the skin or binding sites in
`the keratin. Corticosteroids for the topical treatment of inflammatory, aller-
`gic, and pruritic skin conditions can be made more suitable for topical absorp-
`tion by esterification or acetonidation. For example, both fluocinolone ace-
`tonide (8.10, R = H) and fluocinonide (8.10, R = COCH3) are prodrugs used
`for inflammatory and pruritic manifestations. Once absorbed through the skin
`an esterase releases the drug.
`
`CH3 N.
`N
`
`N
`
`CI
`
`8.9
`
`F
`8.10
`Dipivaloylepinephrine (dipivefrin; 8.11, R = Me3CCO), a prodrug for the
`antiglaucoma drug epinephrine (8.11, R = H), is better able to penetrate the
`cornea than is epinephrine. The cornea and aqueous humor have significant
`esterase activity .20
`
`RO
`
`RO
`
`NHCH3
`
`8.11
`
`c. Prodrugs for Site Specificity. The targeting of drugs for a specific site in
`the body by conversion to a prodrug is plausible when the physicochemical
`properties of the parent drug and prodrug are optimal for the target site. It
`should be kept in mind, however, that when the lipophilicity of a drug is
`increased, it will improve passive transport of the drug nonspecifically to all
`tissues.
`Oxyphenisatin (8.12, R = H) is a bowel sterilant that is active only when
`administered rectally. However, when the hydroxyl groups are acetylated
`(8.12, R = Ac), the prodrug can be administered orally, and it is hydrolyzed
`at the site of action in the intestines to oxyphenisatin.
`One important membrane that often is targeted for drug delivery is the
`blood—brain barrier, a unique lipidlike protective barrier that prevents hydro-
`philic compounds from entering the brain unless they are actively trans-
`ported.21 The blood—brain barrier also contains active enzyme systems to
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`
`8. Prodrugs and Drug Delivery Systems
`
`R 0
`
`OR
`
`O
`
`N
`H
`
`8.12
`protect the central nervous system even further. Consequently, molecular
`size and lipophilicity are often necessary, not sufficient, criteria for gaining
`entry into the brain.22 Also, once the drug has entered the brain, it must be
`modified so that it does not escape.
`Bodor and co-workers have devised a reversible redox drug delivery sys-
`tem for getting drugs into the central nervous system and then, once in,
`preventing their efflux.22,23 The approach is based on the attachment of a
`hydrophilic drug to a lipophilic carrier (a dihydropyridine, 8.13) thereby mak-
`ing the bipartate prodrug overall lipophilic (Scheme 8.4). Once inside the
`brain, the lipophilic carrier is converted enzymatically to a highly hydrophilic
`species (8.14), which is then enzymatically hydrolyzed back to the drug and
`N-methylnicotinic acid (8.15) which is eliminated from the brain. The XH
`group on the drug is an amino, hydroxyl, or carboxyl group. When it is a
`carboxylic acid, the linkage is an acyloxymethyl ester (8.16), which decom-
`poses by the reaction shown in Scheme 8.5. The oxidation of the dihydropyri-
`dine (8.13) to the pyridinium ion (8.14) (half-life generally 20-50 min) prevents
`the drug from escaping out of the brain because it becomes charged. This
`drives the equilibrium of the lipophilic precursor (8.13) throughout all of the
`tissues of the body to favor the brain. Any oxidation occurring outside of the
`brain produces a hydrophilic species that can be rapidly eliminated from the
`body (see Chapter 7). The released oxidized carrier (8.15) is relatively non-
`
`0 (cid:9)
`
`Drug—X (cid:9)
`
`I (cid:9)
`
`I
`
`crosses Drug—X (cid:9)
`(cid:9) blood-brain (cid:9)
`barrier
`
`CH3 (cid:9)
`8.13
`
`I (cid:9)
`
`I (cid:9)
`
`CH3 (cid:9)
`
`0 (cid:9)
`
`0
`
`enzyme Drug—X)
`oxidation w
`
`CH3
`
`8.14
`
`enzyme
`hydrolysis
`
`HOOC
`
`+ Drug — XH
`
`1+
`
`CH3
`
`8.15
`Scheme 8.4. Redox drug delivery system.
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`
`I
`
`IC
`
`+ HO
`
`H
`Drug —C (cid:9) 0 CH2-0-
`
`—carrier
`
`esterase
`
`II. Mechanisms of Prodrug Activation
`
`0
`I I
`Drug—C—OCH2-0—C— carrier
`
`8.16
`
`fast —CH20
`
`Drug—COO-
`Scheme 8.5. Hydrolysis of acyloxymethyl esters.
`
`toxic and easily eliminated from the brain. Although this is a carrier-linked
`prodrug, it requires enzymatic oxidation to target the drug to the brain. The
`oxidation reaction is a bioprecursor reaction (see Section II,B,2,c).
`An example of this approach is the brain delivery of 13-lactam antibiotics for
`the possible treatment of bacterial meningitis. The difficulty in purging the
`central nervous system of infections arises from the fact that the cerebro-
`spinal fluid contains less than 0.1% of the number of immunocompetent leuko-
`cytes found in the blood and almost no immunoglobins; consequently, anti-
`body generation to these foreign organisms is not significant. Since the
`f3-lactam antibiotics are hydrophilic, they enter the brain very slowly, but they
`are actively transported back into the blood. Therefore, they are not as effec-
`tive in the treatment of brain infections as elsewhere. Bodor and co-workers24
`prepared a variety of penicillin prodrugs attached to the dihydropyridine car-
`rier through various linkers (8.17) and showed that f3-lactam antibiotics could
`be delivered in high concentrations into the brain.
`
`8.17
`
`As was discussed in Section V,C,3,a of Chapter 5, increasing the brain
`concentration of the inhibitory neurotransmitter y-aminobutyric acid (GABA)
`results in anticonvulsant activity. However, GABA is too polar to cross the
`blood—brain barrier, so it is not an effective anticonvulsant drug. In order to
`increase the lipophilicity of GABA, a series of y-aminobutyric acid and
`y-aminobutyric Schiff bases were synthesized." Progabide (8.3) emerged as
`an effective lipophilic analog of GABA that crosses the blood—brain barrier,
`releases GABA inside the brain, and shows anticonvulsant activity.25
`Another related approach for anticonvulsant drug design was the synthesis
`of a glyceryl lipid (8.18, R = linolenoyl) containing one GABA molecule and
`one vigabatrin molecule, a mechanism-based inactivator of GABA amino-
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`8. Prodrugs and Drug Delivery Systems
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`transferase and anticonvulsant drug (see Section V,C,3,a of Chapter 5).26 This
`compound inactivates GABA aminotransferase in vitro only if brain esterases
`are added to cleave the vigabatrin from the glyceryl lipid. It also is 300 times
`more potent than vigabatrin, in vivo, presumably because of its increased
`ability to enter the brain.
`
`OCOR
`
`O
`
`O
`) (cid:9)
`0
`
`8.18
`
`NH2
`
`NH2
`
`In the above examples, the lipophilicity of the drugs was increased so that
`they could diffuse through various membranes. Another approach for site-
`specific drug delivery is to design a prodrug that requires activation by an
`enzyme found predominantly at the desired site of action. For example, tumor
`cells contain a higher concentration of phosphatases and amidases than do
`normal cells. Consequently, a prodrug of a cytotoxic agent could be directed
`to tumor cells if either of these enzymes was important to the prodrug activa-
`tion process. Diethylstilbestrol diphosphate (8.19, R = POi-) was designed
`for site-specific delivery of diethylstilbestrol (8.19, R = H) to prostatic carci-
`noma tissue.2,27 In general, though, this tumor-selective approach has not
`been very successful because the appropriate prodrugs are too polar to reach
`the enzyme site, the relative enzymatic selectivity is insufficient, and the
`tumor cell perfusion rate is too poor.
`
`OR
`
`d. Prodrugs for Stability. Some prodrugs protect the drug from the first-
`pass effect (see Section I of Chapter 7). Propranolol (8.20, R = R' = H) is a
`widely used antihypertensive drug, but because of first-pass elimination an
`oral dose has a much lower bioavailability than does an intravenous injec-
`tion. The major metabolites (see Chapter 7) are propranolol 0-glucuronide
`(8.20, R = H, OR' = glucuronide), p-hydroxypropranolol (8.20, R = OH,
`R' = H), and its 0-glucuronide (8.20, R = OH, OR' = glucuronide). The
`hemisuccinate ester of propranolol (8.20, R = H, R' = COCH2CH2COOH)
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`365
`
`was prepared to block glucuronide formation; following oral administration of
`propranolol hemisuccinate, the plasma levels of propranolol were 8 times
`greater than when propranolol was used.28
`
`0"---'N',----'"NHCH(CH3)2
`OR'
`
`R
`
`8.20
`Naltrexone (8.21, R = H), used in the treatment of opioid addiction, is
`nonaddicting and is well absorbed from the gastrointestinal tract. However, it
`undergoes extensive first-pass metabolism when given orally. Ester prodrugs,
`namely, the anthranilate (8.21, R = CO-o-NO2Ph) and the acetylsalicylate
`(8.21, R = CO-o-AcOPh), enhanced the bioavailability 45- and 28-fold, re-
`spectively, relative to 8.21 (R = H).29
`
`8.21
`
`e. Prodrugs for Slow and Prolonged Release. The utility of slow and pro-
`longed release of drugs is severalfold. (1) It reduces the number and frequency
`of doses required. (2) It eliminates nighttime administration of drugs. (3)
`Because the drug is taken less frequently, slow, prolonged release minimizes
`patient noncompliance. (4) When a fast released drug is taken, there is a rapid
`surge of the drug throughout the body. As metabolism of the drug proceeds,
`the concentration of the drug diminishes. A slow release drug would eliminate
`the peaks and valleys of fast released drugs which are a strain On cells. (5)
`Because a constant lower concentration of the drug is being released, it re-
`duces the possibility of toxic levels of drugs. (6) It reduces gastrointestinal
`side effects. A common strategy in the design of slow release prodrugs is to
`make a long chain aliphatic ester because these esters hydrolyze slowly.
`Prolonged release drugs are quite important in the treatment of psychoses
`because these patients require medication for extended periods of time and
`often show high patient noncompliance rates. Haloperidol (8.22, R = H) is a
`potent, orally active central nervous system depressant, sedative, and tran-
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`8. Prodrugs and Drug Delivery Systems
`
`quilizer. However, peak plasma levels are observed between 2 and 6 hr after
`administration. Haloperidol decanoate [8.22, R = CO(CH2)8CH3], however,
`is injected intramuscularly as a solution in sesame oil and its antipsychotic
`activity lasts for about 1 month.3° The antipsychotic fluphenazine (8.23,
`R = H) also has a short duration of activity (6-8 hr). Fluphenazine enanthate
`[8.23, R = CO(CH2)5CH3] and fluphenazine decanoate [8.23, R =
`CO(CH2)8CH3], however, have durations of activity of about a month.31
`
`CF3
`
`8.22
`
`OR
`
`8.23
`
`Conversion of the nonsteroidal anti-inflammatory (antiarthritis) drug
`tolmetin sodium (8.24, R = 0- Na+) to the corresponding glycine conjugate
`(8.24, R = NHCH2COOH) increases the potency and extends the peak con-
`centration of tolmetin from l to about 9 hrs because of the slow hydrolysis of
`the prodrug amide linkage.32
`
`(cid:9) 0
`I
`CH3-K
`
`
`
`0
`I I
`CH2C-R
`
`CH3
`
`8.24
`
`f. Prodrugs to Minimize Toxicity. The prodrugs that were designed for
`improved absorption (Section II,A,2,b), for site specificity (Section II,A,2,c),
`for stability (Sectio