Drugs of the Future 1991, 16(5): 443-458
`Copyright PROUS SCIENCE
`
`Review Article
`
`Novel chemical approaches in prodrug design
`
`Hans Bundgaard
`Royal Danish School of Pharmacy,
`Department of Pharmaceutical Chemistry,
`2 Universitetsparken, DK-2100 Copenhagen, Denmark
`
`CONTENTS
`
`Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443
`Ester prodrugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444
`Double esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444
`Biolabile glycolamide esters
`. . . . . . . . . . . . . . . . . . . . . . 445
`Water-soluble ester prodrugs . . . . . . . . . . . . . . . . . . . . . . 446
`Prodrug derivatives of amines . . . . . . . . . . . . . . . . . . . . . . . 448
`Prodrug forms for an ester function . . . . . . . . . . . . . . . . . . . 448
`The double prodrug concept . . . . . . . . . . . . . . . . . . . . . . . . . 450
`Pilocarpine prodrugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
`Acyclovir prodrugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
`Prodrug derivatives of peptides . . . . . . . . . . . . . . . . . . . . . . 452
`Bioreversible derivatization of the peptide bond . . . . . . . . 452
`4-lmidazolidinone derivatives . . . . . . . . . . . . . . . . . . . . . . 454
`Prodrugs of TRH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
`Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456
`References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456
`
`Introduction
`
`Prodrug design comprises an area of drug research that
`is concerned with the optimization of drug delivery. A pro-
`
`drug is a pharmacologically inactive derivative of a parent
`drug molecule that requires spontaneous or enzymatic
`transformation within the body in order to release the active
`drug, and that has improved delivery properties over the
`parent drug molecule.
`A molecule with optimal structural configuration and phy(cid:173)
`sicochemical properties for eliciting the desired therapeutic
`response at its target site does not necessarily possess the
`best molecularform and properties for its delivery to its point
`of ultimate action. Usually, only a minor fraction of doses ad(cid:173)
`ministered reach the target area and since most agents in(cid:173)
`teract with non-target sites as well, an inefficient delivery
`may result in undesirable side effects. This fact of differ(cid:173)
`ences in transport and in situ effect characteristics for many
`drug molecules is the basic reason why bioreversible chem(cid:173)
`ical derivatization of drugs, i.e, prodrug formation, is a
`means by which a substantial improvement in the overall ef(cid:173)
`ficacy of drugs can often be achieved.
`Prodrugs are designed to overcome pharmaceutically
`and/or pharmacokinetically based problems associated
`with the parent drug molecule that would otherwise limit the
`clinical usefulness of the drug. The prodrug approach can
`
`Drug
`
`Pro
`
`+
`
`Pro-moiety
`
`Enzymatic or
`nonenzymatic
`
`---b~iotr•nrrmat,...io_n __ __
`
`Pro
`
`Drug
`
`Fig. 1. Schematic illustration of the prodrug concept as a means of improving drug absorption.
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2015 - 0001
`
`

`
`444
`
`Novel chemical approaches in prodrug design
`
`be illustrated as shown in Figure 1. The usefulness of a drug
`molecule is limited by its suboptimal physicochemical prop(cid:173)
`erties, e.g., it shows poor biomembrane permeability. By at(cid:173)
`tachment of a pro-moiety to the molecule or otherwise modi(cid:173)
`fying the compound, a prod rug is formed that overcomes the
`barrier for the drug's usefulness. Once past the barrier, the
`prod rug is reverted to the parent compound by a post-barri(cid:173)
`er enzymatic or non-enzymatic process. Prod rug formation
`can thus be considered as conferring a transient chemical
`cover to alter or eliminate undesirable properties of the par(cid:173)
`ent molecule.
`The prodrug approach has been successfully applied to
`a wide variety of drugs. Most of the applications have in(cid:173)
`volved: 1) enhancement of bioavailability and passage
`through various biological barriers, 2) increased duration of
`pharmacological effects, 3) increased site-specificity, 4) de(cid:173)
`creased toxicity and adverse reactions, 5) improvement of
`organoleptic properties, and 6) improvement of stability and
`solubility properties (1-6).
`A basic requisite for the prod rug approach to be useful in
`solving drug delivery problems is the ready availability of
`chemical derivative types satisfying the prodrug require(cid:173)
`ments, the most prominent of these being reconversion of
`the prodrug to the parent drug in vivo. This prodrug-drug
`conversion may take place before absorption (e.g., in the
`gastrointestinal tract), during absorption, after absorption or
`at the specific site of drug action in the body, all dependent
`upon the specific goal for which the prodrug is designed.
`Ideally, the prod rug should be converted to the drug as soon
`as the goal is reached. The prodrug per se is an inactive
`species and therefore, once its job is completed, intact pro(cid:173)
`drug represents unavailable drug. For example, prodrugs
`designed to overcome solubility problems in formulating in(cid:173)
`travenous injection solutions should preferably be con(cid:173)
`verted immediately to drug following injection so that the
`concentration of circulating prodrug would rapidly become
`insignificant in relation to that of the active drug. Conversely,
`if the objective of the prod rug is to produce a sustained drug
`action through rate-limiting prodrug conversion, the rate of
`the conversion should not be too high.
`The necessary conversion or activation of prod rugs to the
`parent drug molecules in the body can take place by a vari(cid:173)
`ety of reactions. The most common prodrugs are those re(cid:173)
`quiring a hydrolytic cleavage mediated by enzymatic cataly(cid:173)
`sis. Active drug species containing hydroxyl or carboxyl
`groups can often be converted to prodrug esters from which
`the active forms are regenerated by esterases within the
`body, e.g., in the blood or liver. In other cases, active drug
`substances are regenerated from their prodrugs by bio(cid:173)
`chemical reductive or oxidative processes.
`Besides usage of the various enzyme systems of the body
`to carry out the necessary activation of prodrugs, the buff(cid:173)
`ered and relatively constant value of the physiological pH
`(7.4) may be useful in triggering the release of a drug from
`a prodrug. In these cases, the prodrugs are characterized
`by a high degree of chemical !ability at pH 7.4, while prefer(cid:173)
`ably exhibiting a higher stability at, for example, pH 3-4. A
`serious drawback of prodrugs requiring chemical (non-en(cid:173)
`zymatic) release of the active drug is the inherent !ability of
`the compounds, raising some stability-formulation prob(cid:173)
`lems at least in cases of solution preparations. As will be
`shown later, such problems have, in particular cases, been
`
`overcome by using a more sophisticated approach involving
`pro-prodrugs or double prodrugs, where use is made of an
`enzymatic release mechanism prior to the spontaneous
`reaction.
`In recent years several types of bioreversible derivatives
`have been exploited for utilization in designing prodrugs (7,
`8). An account of novel chemical approaches in the design
`of prodrugs is given in the following.
`
`Ester prodrugs
`
`The popularity of using esters as a prodrug type for drugs
`containing carboxyl or hydroxyl functions stems primarily
`from the fact that the organism is rich in enzymes capable
`of hydrolyzing esters. The distribution of esterases is ubiqui(cid:173)
`tous and several types can be found in the blood, liver and
`other organs or tissues. In addition, by appropriate esterifi(cid:173)
`cation of molecules containing a hydroxyl or caboxyl group
`it is feasible to obtain derivatives with almost any desirable
`hydro- or lipophilicity as well as in vivo !ability, the latter being
`dictated by electronic and steric factors. Accordingly, a great
`number of alcoholic or carboxylic acid drugs have been mo(cid:173)
`dified for a multitude of reasons using the ester prod rug ap(cid:173)
`proach (7).
`Sometimes, however, many aliphatic or aromatic esters
`are not sufficiently labile in vivo to ensure a sufficiently high
`rate and extent of prodrug conversion. For example, simple
`alkyl and aryl esters of penicillins are not hydrolyzed to the
`active free penicillin acid in vivo and therefore have no thera(cid:173)
`peutic potential (9). The reason for this is the highly sterically
`hindered environment about the carboxyl group in the peni(cid:173)
`cillin molecule which makes enzymatic attack on the acyl
`group very difficult.
`
`Double esters
`
`This shortcoming can be overcome by preparing a double
`ester type, (acyloxy)alkyl or [(alkoxycarbonyl)oxy]alkyl es(cid:173)
`ters in which the terminal ester grouping is less sterically hin(cid:173)
`dered. The first step in the hydrolysis of such an ester is en(cid:173)
`zymatic cleavage of the terminal ester bond with formation
`of a highly unstable hydroxymethyl ester which rapidly dis(cid:173)
`sociates to the parent acidic drug and formaldehyde
`(Scheme 1).
`This principle has been used successfully to improve the
`oral bioavailability of ampicillin (1 ), and no fewer than three
`ampicillin prodrug forms are now on the market, namely the
`pivaloyloxymethyl ester{2) (pivampicillin), the ethoxycarbo(cid:173)
`nyloxyethyl ester (3) (bacampicillin), and the phthalidyl ester
`(4) (talampicillin) (for a review, see ref. 9). Bacampicillin con(cid:173)
`tains a terminal carbonate ester moiety and releases etha(cid:173)
`nol, carbon dioxide and acetaldehyde upon hydrolysis. In ta(cid:173)
`lampicillin the pro-moiety released upon hydrolysis is
`2-carboxybenzaldehyde which is further metabolized to
`2-hydroxymethylbenzoic acid.
`In more recent years the applicability of this double ester
`concept in prodrug design has been further expanded.
`Thus, similar esters have been prepared from various
`non-steroidal antiinflammatory agents as well as from me(cid:173)
`thyldopa (10), cromoglycic acid (11 ), furosemide (12) and
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2015 - 0002
`
`

`
`Drugs Fut 1991, 16(5)
`
`445
`
`Scheme 1
`
`0
`0
`II
`II
`Drug- C- 0- CH- 0- C- A
`I
`2
`R1
`
`enzymic ...
`
`+ ~-COOH
`
`0
`II
`Drug- C- 0- CHOH
`I
`R1
`
`! fast
`
`Drug-COOH
`
`membranes by passive diffusion and then revert by enzy(cid:173)
`matic cleavage of the protective group to the parent phos(cid:173)
`phomonoester. Reports about the application of this pro(cid:173)
`drug approach
`to biologically
`important nucleotides
`certainly may soon appear.
`
`(1)
`
`(2)
`
`(3)
`
`(4)
`
`A=H
`A= - CH20- C- C(CH3b
`I(
`0
`
`A= - CHO- C-OCH2CH3
`I
`II
`CH3
`0
`
`A= so
`
`(5)
`
`(6)
`
`A= H
`
`A= - CH20-fi- CH2CH2CH3
`0
`
`nalidixicacid (13), and found to be useful as prod rugs for en(cid:173)
`hancement of the dermal or oral delivery of these acidic
`drugs. The advantage of such esters in terms of enzymatic
`!ability can be illustrated with nalidixic acid (5). Whereas the
`methyl ester shows less than 5% hydrolysis upon incubation
`in human plasma for 24 h, the butyryloxymethyl ester (6) is
`rapidly hydrolyzed, the half-life being 8 min (13).
`The applicability of a-acyloxyalkyl esters as biologically
`reversible transport forms has been extended to include the
`phosphate group and phosphonic acids (8). Both the chemi(cid:173)
`cal and enzyme-mediated hydrolysis of bis(acyloxymethyl)
`esters of phosphomonoesters take place as shown in
`Scheme 2, with the intermediate formation of a monoacylox(cid:173)
`ymethyl ester (14, 15). The 0-hydroxymethyl derivatives
`formed upon ester hydrolysis have only a transitory exis(cid:173)
`tence and spontaneously eliminate one molecule of formal(cid:173)
`dehyde. The bis(acyloxymethyl) ester derivatives are neu(cid:173)
`tral compounds, and they can conceivably traverse cell
`
`Biolabile glycolamide esters
`
`An alternative solution to the problem of obtaining enzy(cid:173)
`matically labile ester prodrugs of carboxylic acid agents is
`provided by N,N-disubstituted glycolamide esters. Such es(cid:173)
`ters have recently been shown to be cleaved with remark(cid:173)
`able speed in human plasma, the responsible enzyme being
`pseudocholinesterase (Scheme 3) (16-18). As seen from
`the examples listed in Table I, such esters derived from vari(cid:173)
`ous carboxylic acids are hydrolyzed much more facilely than
`the corresponding simple methyl or ethyl esters. The glyco(cid:173)
`lamide esters combine a high susceptibility to undergo en(cid:173)
`zymatic hydrolysis in plasma with a high stability in aqueous
`solution and furthermore, this new ester prodrug type is
`characterized by providing ample possibilities for varying
`the water and lipid solubilities of the derivatives with retain(cid:173)
`ment of the favorable enzymatic/nonenzymatic hydrolysis
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2015 - 0003
`
`

`
`446
`
`Novel chemical approaches in prodrug design
`
`Scheme 2
`
`fast
`
`'"" ! -cH2o
`
`Scheme 3
`
`Table I: Half-lives (t112) of hydrolysis of esters of various drugs and
`compounds containing a carboxylic acid function in 80% human
`plasma (pH 7.4, 37°C) (16, 19).
`
`Acid
`
`Salicylic acid
`
`4-Aminobenzoic acid
`
`Ketoprofen
`
`Fenbufen
`
`Tolmetin
`
`Tolfenamic acid
`
`lndomethacin
`
`Naproxen
`
`Furosemide
`
`Tranexamic acid
`
`L-Tyrosine
`
`T1/2
`
`Methyl ester
`
`N,N-Diethylglycola-
`mide ester
`
`17.6 h
`
`>100 h
`
`>20 h
`
`4.7 h
`
`19 h
`
`100 h
`
`150 h
`
`20 h
`
`>100 h
`
`4.0 h
`
`1.0 h
`
`0.80 min
`
`0.6min
`
`0.5min
`
`3.8 min
`
`13.4 min
`
`5.0 min
`
`25 min
`
`0.6min
`
`4.4 h
`
`1.2 min
`
`0.5min
`
`no acid esters (7). The ideal properties of such prod rugs are
`as follows: they should possess a high water solubility at the
`pH of optimal stability and sufficient stability in aqueous so(cid:173)
`lution to allow long-term storage (>2 years) of ready-to-use
`solutions and yet they should be converted quantitatively
`and rapidly in vivo to the active parent drug. However, none
`of these derivatives may often fully satisfy all these require(cid:173)
`ments. Thus, whereas a-amino acid esters or related
`short-chained aliphatic amino acid esters are in general
`readily hydrolyzed enzymatically, they exhibit a very poor
`stability in aqueous solution, making it impossible to prepare
`ready-to-use solutions (7).
`The major reason for the high instability' of a-amino and
`short-chained aliphatic amino acid esters in aqueous solu(cid:173)
`tion at pH values affording their favorable water-solubility
`
`0
`II
`R1
`Drug-COOH + HOCH - C- ~
`~
`2
`
`index. One obvious area of application of this ester prodrug
`type concerns nonsteroid antiinflammatory drugs (19, 20).
`Esterification of these carboxylic acid agents is known to re(cid:173)
`duce their gastric ulcerogenic activity. However, simple alkyl
`esters of these agents are inefficiently cleaved in the organ(cid:173)
`ism and are often also highly insoluble in water. In contrast,
`the glycolamide esters have a high capacity to release the
`parent active drugs following absorption and possess physi(cid:173)
`cochemical properties favorable for peroral absorption ( 19).
`
`Water-soluble ester prodrugs
`
`Formation of water-soluble ester prod rugs has long been
`recognized as an effective means of increasing the
`aqueous solubility of drugs containing a hydroxyl group,
`aimed at developing improved preparations for parenteral
`or ophthalmic administration. The most commonly used es(cid:173)
`ters for increasing the aqueous solubility of hydroxyl-con(cid:173)
`taining agents are esters containing an ionizable group, i.e.,
`dicarboxylic acid hemiesters, phosphate esters and a-ami-
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2015 - 0004
`
`

`
`Drugs Fut 1991, 16(5)
`
`447
`
`Scheme 4
`
`..
`-oR9
`
`0
`II r:..
`
`c1-0R
`
`N-
`I
`
`(~
`C.rlH
`<t:OR
`
`N,
`I
`
`0
`c~
`
`oe~
`cc )0
`
`OR
`Hcf ....__1
`
`~,..H
`N,
`I
`
`0
`II
`
`CC-OH
`
`N-
`I
`
`(i.e., pH 3-5) is partly due to the strongly electron-withdraw(cid:173)
`ing effect of the protonated amino group which activates the
`ester linkage toward hydroxide ion attack and partly (and
`predominantly) to intramolecular catalysis or assistance by
`the neighboring amino group of ester hydrolysis (21, 22).
`The mechanisms involved include intramolecular nucleo(cid:173)
`philic catalysis, intramolecular general-base catalysis or
`general-base specific base catalysis, as depicted in
`Scheme4.
`It has recently been shown (23) that an effective and sim(cid:173)
`ple means to totally block the hydrolysis-facilitating effect of
`the amino group and yet retain a rapid rate of enzymatic es(cid:173)
`ter hydrolysis is to incorporate a phenyl group between the
`ester moiety and the amino group. By doing so the intramo(cid:173)
`lecular catalytic reactions of the amino group, as outlined in
`Scheme 4, are no longer possible for steric reasons and fur(cid:173)
`thermore, the ester-labilizing effect of the protonated amino
`group due to its polar character is greatly diminished. Be(cid:173)
`cause of the requirement of a pKa value greater than 5-6 for
`the amino group (for solubility reasons), the group is not di(cid:173)
`rectly attached to the phenyl nucleus but separated from this
`by an alkylene group, in the most simple case a methylene
`group. Such N-substituted 3- or 4-aminomethylbenzoate
`esters (7) have been found to be readily soluble (often
`>25%) in water at weakly acidic pH values and to possess
`a very high stability in such solutions combined with a high
`susceptibility to undergo enzymatic hydrolysis in the pres(cid:173)
`ence of plasma (Scheme 5) (23). Thus, the 4-(morpholino(cid:173)
`methyl)benzoate ester of metronidazole (8) possesses a
`shelf-life of more than 1 O years in aqueous solution of pH 4
`and 25°C while being hydrolyzed to metronidazole (9) in hu(cid:173)
`man plasma with a half-life of 0.4 min (Scheme 6). The pKa
`of the morpholino group in compound (8) is 6.1 and readily
`water-soluble salts can be formed with e.g., hydrochloric
`acid (24). Similar esters with the same favorable solubility,
`in vitro stability and in vivo !ability characteristics have been
`described for various corticosteroids (23), chloramphenicol
`
`Schemes
`
`Drug- 0- C
`II
`0
`
`(7)
`
`2
`
`R,
`
`R2
`
`-OCH-~
`!
`
`Drug-OH
`
`+
`
`(25), acyclovir (23), ganciclovir and other hydroxyl-contain(cid:173)
`ing drugs (23, 26}
`These properties regarding solubility, chemical stability
`and enzymatic !ability make N-substituted aminomethyl(cid:173)
`benzoate esters a promising new prodrug type for slightly
`soluble drugs containing an esterifiable hydroxyl group. In
`addition to being useful for parenteral or ophthalmic admin(cid:173)
`istration, these novel prodrugs may be applied to improve
`the peroral, rectal or dermal bioavailability of slightly wa(cid:173)
`ter-soluble drugs. In this regard, it should be noted that the
`lipophilicity of the prodrug derivatives can readily be modi(cid:173)
`fied or controlled by the appropriate selection of the amino
`group both in terms of amine basicity and hence degree of
`ionization at physiological pH, and in terms of hydrophobic(cid:173)
`ity of the substituents on the nitrogen atom. It has thus been
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2015 - 0005
`
`

`
`448
`
`Novel chemical approaches in prodrug design
`
`Scheme 6
`
`...
`
`(8)
`
`(9)
`
`found (27) that the 3-(dipropylaminomethyl)benzoate ester
`of acyclovir, besides being much more soluble than acyclo(cid:173)
`vir in water at pH 3-5, is more lipophilic than the parent drug
`at pH 7.4. Whereas acyclovir shows a log P value of -1.47,
`the value for the ester is 0.60 (P is the partition coefficient
`between octanol and phosphate buffer of pH 7.4).
`It may be added that this prodrug approach can also be
`used for drugs containing an NH-acidic group (e.g., hydan(cid:173)
`toins, imides, secondary amides, imidazoles) by forming
`N-acloxymethyl derivatives (23). From such derivatives the
`parent drug is regenerated via a two-step reaction: Enzy(cid:173)
`matic cleavage of the ester grouping followed by a sponta(cid:173)
`neous and fast decomposition of the N-hydroxymethyl inter(cid:173)
`mediate
`(Scheme 7). Such prodrug derivatives of
`allopurinol have been found to possess improved parenteral
`and rectal delivery characteristics as a result of the in(cid:173)
`creased aqueous solubility (28).
`
`Scheme 7
`
`enzymatic
`
`l fast
`
`Prodrug derivatives of amines
`
`N-Acylation of amines to give amide prodrugs has only
`been used to a limited extent due to the relative stability of
`
`amides in vivo (7). Similarly, the utility of carbamates as pro(cid:173)
`d rug derivatives for amines is limited for the same reason.
`By introducing an enzymatically hydrolyzable ester function
`in the carbamate structure it is, however, possible to circum(cid:173)
`vent this problem. Thus, N-(acyloxyalkoxycarbonyl) deriva(cid:173)
`tives of primary or secondary amines may be readily trans(cid:173)
`formed to the parent amine in vivo (29-31). Enzymatic
`hydrolysis of the ester moiety in such derivatives would lead
`to a (hydroxyalkoxy)carbonyl derivative which sponta(cid:173)
`neously decomposes into the parent amine via an unstable
`carbamic acid (Scheme 8).
`Such (acyloxy}alkyl carbamates may be promising biola(cid:173)
`bile prodrugs for amino functional drugs, since they are neu(cid:173)
`tral compounds and combine a high stability in aqueous so(cid:173)
`lution (32} with a high susceptibility to undergo enzymatic
`regeneration of the parent amine by ester hydrolysis (31 ).
`For primary amines, however, an intramolecular acyl trans(cid:173)
`fer reaction leading to the formation of a stable N-acylated
`parent amine may compete with the reaction sequence in
`Scheme 8 at physiological pH and thus diminish the yield of
`amine regenerated. Such intramolecular N-acylation is
`structurally impossible in the derivatives of secondary
`amines. Therefore, the utility of N-acyloxyalkoxycarbonyl
`derivatives as prod rugs of primary amines relies on a 'high
`rate of enzymatic hydrolysis to compete with the undesired
`intramolecular recation (31 ).
`This prodrug approach has been applied to various
`~-blockers, including timolol and betaxolol, and found to be
`useful in improving the in vitro corneal permeation of these
`antiglaucoma agents (30).
`Another recently developed prodrug type for the amino
`groups is N-Mannich bases formed with 0-acyloxymethyl
`salicylamide (33). Such compounds show a reasonable sta(cid:173)
`bility in weakly acidic solutions but are readily cleaved enzy(cid:173)
`matically by a two step reaction: enzymatic hydrolysis of the
`ester group followed by a spontaneous (non-enzymatic) de(cid:173)
`composition of the salicylamide N-Mannich base with re(cid:173)
`lease of the parent amine (Scheme 9).
`
`Prodrug forms for an ester function
`
`As noted above, esters are probably the best known pro(cid:173)
`drug derivatives for drugs containing carboxyl or hydroxyl
`groups. Numerous drugs contain an ester group as an es(cid:173)
`sential part of their structure, e.g., various calcium antago(cid:173)
`nists like nifedipine and nicardipine, anticholinergic agents
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2015 - 0006
`
`

`
`Drugs Fut 1991, 16(5)
`
`449
`
`Scheme 8
`
`Drug- NH- C- 0- CH- 0- C- R2
`II
`II
`I
`0
`0
`R1
`
`Drug-NH-C-0-CH-OH
`II
`I
`0
`R1
`
`+ ~-COOH
`
`...
`
`Drug- NH- COOH
`
`+ R1-CHO
`
`!
`
`Scheme 9
`
`0
`II
`rAYC- NH- CH2- NH-Drug
`~OH
`
`fast
`
`0
`II
`rAYC-NH2
`
`~OH
`
`+ HCHO + Drug-NH2
`
`and steroid derivatives, but until recently no bioreversible
`derivatives for the ester groups have been explored. Studies
`in our laboratory have shown that N-sulfonyl imidates may
`be a suitable prodrug type (34, 35). Such compounds were
`found to be rapidly hydrolyzed by plasma enzymes to yield
`a sulfonamide and ester in quantitative amounts (Scheme
`1 O). By varying the sulfonyl portions of the derivatives it is
`
`possible to control such physicochemical properties as wa(cid:173)
`ter solubility and lipophilicity.
`It is of interest to note that besides being considered as a
`prod rug type for carboxylic acid esters, N-sulfonyl imidates
`can also be thought of as a prod rug type for primary sulfano(cid:173)
`mides, in which case the ester component would act as the
`pro-moiety.
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2015 - 0007
`
`

`
`450
`
`Novel chemical approaches in prodrug design
`
`Scheme 10
`
`l
`
`The double prodrug concept
`
`Although the prod rug approach generally is a most useful
`means to improve the delivery of various drugs, the usual
`strategy of preparing a bioreversible derivative may some(cid:173)
`times fail. For example, a prodrug designed to promote
`site-specific delivery through a target-specific cleavage
`mechanism (e.g., due to an atypical enzyme activity) may
`not be successful if it is not able to reach the target tissue.
`Both conditions should be fulfilled at the same time (36, 37).
`Consider also a prod rug where the necessary conversion to
`the parent drug in vivo is triggered by the buffered and rela(cid:173)
`tively constant value of the physiological pH of 7.4. A serious
`drawback of such prodrugs requiring chemical (non-enzy(cid:173)
`matic) release of the active drugs is the inherent !ability of
`the derivatives, producing some stability-formulation prob(cid:173)
`lems at least in cases of solution preparations.
`A promising means of optimizing the properties of pro(cid:173)
`drugs and to overcome various drawbacks of these involves
`cascade
`latentiation or the double prodrug concept
`(pro-prodrugs) (8). Thus, it should be possible to overcome
`the. stability problem of the prodrug considered above by
`denvatizing it in such a manner that an enzymatic release
`mechanism is required prior to the spontaneous release of
`the parent drug (Fig. 2). As outlined in Figure 3, the concept
`may also be useful in achieving drug targeting by preparing
`a prodrug form with good transport properties of a prodrug
`which exhibits a site-specific bioactivation. The potential
`utility of the double prodrug concept is illustrated with two
`
`Stability
`
`Pro-Prod rug t Enzymatic
`
`Chemical
`
`Prod rug
`
`Drug
`
`Fig. 2. Stabilization of a spontaneously decomposing prodrug by
`furtherderivatization to yield a chemically stable but enzymatical(cid:173)
`ly labile double prodrug.
`
`examples involving pilocarpine and acyclovir. Other exam(cid:173)
`ples can be found elsewhere (8).
`
`Pilocarpine prodrugs
`
`Pilocarpine (10) is widely used as a topical miotic agent
`for controlling the elevated intraocular pressure associated
`with glaucoma. However, the drug presents significant de(cid:173)
`livery problems. Its ocular bioavailability is low, the elimina(cid:173)
`tion of the drug from its site of action in the eye is fast (result(cid:173)
`ing in a short duration of action) and, furthermore,
`undesirable side effects such as myopia and miosis fre(cid:173)
`quently occur as a result of systemic (noncorneal) absorp(cid:173)
`tion or transient peaks of high drug concentration in the eye.
`These shortcomings of pilocarpine may be overcome by
`the double prodrug approach. To be useful, a potential pro(cid:173)
`drug should exhibit a higher lipophilicity than pilocarpine in
`order to enable an efficient penetration through the corneal
`membrane, should possess sufficient aqueous solubility
`and stability for formulation as eyedrops, should be con(cid:173)
`verted to the active parent drug within the cornea or once the
`corneal barrier has been passed, and should lead to a con(cid:173)
`trolled release and hence prolonged duration of action of pi(cid:173)
`locarpine.
`Various diesters of pilocarpic acid (11) have been shown
`to possess these desirable attributes (38-42). The com(cid:173)
`pounds are highly stable in aqueous solution at pH 5-6 but
`readily converted quantitatively to pilocarpine in the eye
`through a sequential process involving enzymatic hydroly(cid:173)
`sis of the 0-acyl bond followed by a spontaneous ring-clo(cid:173)
`sure of the intermediate pilocarpic acid monoester (12)
`(Scheme 11) (42). The latter derivatives were originally de(cid:173)
`veloped as prodrug forms but they suffered from a limited
`stability in aqueous solution (39). This stability problem was
`solved, however, by forming the double prod rugs pilocarpic
`acid diesters. Because of their blocked hydroxyl group these
`compounds are unable to undergo cyclization to pilocarpine
`in absence of hydrolytic enzymes. Studies in rabbits and
`monkeys have shown that these double prod rugs give rise
`to improved ocular bioavailability of the parent drug as a re(cid:173)
`sult of their greater lipophilicity, and furthermore, result in a
`more prolonged duration of action of pilocarpine (41 ). The
`0-benzoyl pilocarpic acid methyl ester (11, R = CH3; R1 =
`C6H5) has been selected as the prodrug derivative having
`the optimal properties and is presently being clinically tested
`(43).
`
`Acyclovir prodrugs
`
`Acyclovir (13) is a clinically useful antiherpetic agent
`which exhibits great selectivity in its antiviral action through
`conversion to the active triphosphorylated species by virtue
`of virus-specific thymidine kinase (44, 45). Acyclovir is thus
`a prodrug exhibiting a site-specific conversion to the active
`drug. If suffers, however, from poor oral bioavailability, only
`15-20% of an oral dose being absorbed in humans (46, 47).
`This can most likely be ascribed to the poor water-solubility
`(1.2 mg/ml) and lipophilicity of the compound. 6-Deoxyacy(cid:173)
`clovir (desciclovir) (14) (48) has been found to be a promis(cid:173)
`ing prodrug with improved oral absorption (Scheme 12).
`The compound is 18 times more water-soluble than acy-
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2015 - 0008
`
`

`
`Drugs Fut 1991, 16(5)
`
`451
`
`Site-Specific Delivery
`
`Non-Target Sites
`
`Prodrug ~ Drug
`
`Pro-Prod rug
`
`Target Sites
`
`Prod rug
`
`Site-specific
`
`Cleavage
`
`Drug
`
`Prodrug: Site-specific Cleavage, Poor Transport Properties
`Pro-Prodrug: Good Transport Properties
`
`Fig. 3. The use of the double prodrug concept to obtain site-specific delivery through a site-specific cleavage of a prodrug combined with
`its efficient transport to the site of action via a pro-prodrug.
`
`Scheme 11
`
`CH,~_..CH, enzymic
`
`..
`
`N
`
`OR
`
`0
`I
`C:O
`I
`R'
`
`(11)
`
`(12)
`
`(10)
`
`clovir and is also more lipophilic. In vivo it is rapidly oxidized
`by xanthine oxidase to acyclovir. Studies in rats and humans
`have shown that 6-deoxyacyclovir is readily absorbed
`(about 75%) after oral administration (48, 49). The com(cid:173)
`pound is also susceptible to undergo oxidation by aldehyde
`oxidase to give the inactive 8-hydroxy-6-deoxyacyclovir, but
`this non-activating oxidation plays only a minor role in com-
`
`parison to the activating oxidation by xanthine oxidase (50)
`which is present in both the gut and the liver.
`Similar 6-deoxy prodrugs with improved gastrointestinal
`absorption have been prepared from other antiviral acyclo(cid:173)
`nucleosides, especially when combined with esterification
`of hydroxyl group(s) in the 9-position (51, 52). The latter de(cid:173)
`rivatives may thus be considered as triple prodrugs.
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2015 - 0009
`
`

`
`452
`
`Novel chemical approaches in prodrug design
`
`Scheme 12
`
`(14)
`
`I Xanthine
`t oxidase
`
`Acyclovir (13)
`
`! Virus-specific
`
`thymidine kinase
`
`Phosphates
`
`more lipophilic and hence facilitate their absorption. To be
`a useful approach however, the derivatives should be capa(cid:173)
`ble of releasing the parent peptide spontaneously or enzy(cid:173)
`matically in the blood following their absorption.
`This prod rug approach has been studied intensively in our
`laboratory during the past few years (56, 57) and some illus(cid:173)
`trative novel results are presented below.
`
`Bioreversible derivatization of the peptide bond
`
`It is generally recognized that N-alkylation of peptide
`bonds usually makes them resistant to enzymatic attack
`(58, 59). However, since N-methyl and similar alkyl deriva(cid:173)
`tives are not bioreversible, the approach of simple N-alkyla(cid:173)
`tion implies the design of a new peptide (the analog ap(cid:173)
`proach). A possible strategy in a prodrug approach (Fig. 4)
`may be to create an N-a-hydroxyalkyl derivative of the pep(cid:173)
`tide bond since such derivatives of primary and cyclic
`amides are known to be spontaneously converted to the
`parent amide and the corresponding aldehyde in aqueous
`solution, the rate of conversion being dependent on the na(cid:173)
`ture of the alkyl group and the acidity of the am