Recent progress in prodrug design strategies based on generally applicable modifications

Accepted Manuscript Digest Recent progress in prodrug design strategies based on generally applicable modifications Yoshio Hamada PII: DOI: Reference:

S0960-894X(17)30218-4 http://dx.doi.org/10.1016/j.bmcl.2017.02.075 BMCL 24747

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Bioorganic & Medicinal Chemistry Letters

Received Date: Revised Date: Accepted Date:

30 November 2016 27 February 2017 28 February 2017

Please cite this article as: Hamada, Y., Recent progress in prodrug design strategies based on generally applicable modifications, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl. 2017.02.075

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BMCL Digest

Recent progress in prodrug design strategies based on generally applicable modifications Yoshio Hamadaa,b,∗ a b

Faculty of Frontiers of Innovative Research in Science and Technology, Konan University, Minatojima-minamimachi, Chuo, Kobe 650-0043, Japan Fuculty of Pharmaceutical Sciences, Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan

A R T IC LE IN F O

A B S TR A C T

Article history: Received Revised Accepted Available online

The development of prodrugs has progressed with the aim of improving drug bioavailability by overcoming various barriers that reduce drug benefits in clinical use, such as stability, duration, water solubility, side effect profile, and taste. Many conventional drugs act as the precursors of an active agent in vivo; for example, the anti-HIV agent azidothymidine (AZT) is converted into its corresponding active triphosphate ester in the body, meaning that AZT is a prodrug in the broadest sense. However prodrug design is generally difficult owing to the lack of general versatility. Thus, these podrugs, broadly defined, are often discovered by chance or trial-anderror. Recently, many prodrugs that could release the corresponding parent drugs with or without enzymatic action under physiological conditions have been reported. These prodrugs can be easily designed and synthesized because of their generally applicable modifications. This digest paper provides an overview of recent development in prodrug strategies for drugs with a carboxylic acid or hydroxyl/amino group on the basis of a generally applicable modification strategy, such as esterification, amidation, or benzylation.

Keywords: enzyme prodrug spontaneous cleavage bioavailability enzyme

2016 Elsevier Ltd. All rights reserved.

The prodrug strategy is a practical approach to improving drug bioavailability. Prodrugs often overcome various barriers that reduce drug benefits, such as stability, duration, water-solubility, side effect profile, and taste. Many approaches to their design have been outlined. 1-5 In fact, many conventional drugs known to be activated after metabolic modification, such as L-3,4dihydroxyphenylalanine (levodopa), the precursor of the neurotransmitters dopamine, norepinephrine, and epinephrine, could be considered a type of prodrug.6 Anti-viral nucleoside analogue reverse transcriptase inhibitors, such as azidothymidine (AZT), 7 are known to act as corresponding active triphosphate esters, and can also be thought of as prodrugs in the broadest sense. Although the anti-viral agent tenofovir (TFV) also acts as an active triphosphate ester in the body, some prodrugs of tenofovir were developed to improve its bioavailability. One of the TFV prodrugs, tenoforvir alafenamide (TAF), which is a phosphoramide of tenofovir and alanine isopropylester, is stable in human plasma and can release TFV in target cells such as CD4 lymphocytes. 8 TAF is the prodrug of prodrug (TFV), namely a pèro-prodrug. However, the design of prodrugs is generally difficult owing to the lack of general versatility; therefore, most prodrugs, broadly defined, have been discovered by chance or trial-and-error.9 This digest paper describes recent developments

in prodrug design strategies that are generally based on applicable modifications such as esterification, amidation, or

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∗ Corresponding author. Tel.: +81-78-303-1418; e-mail: [email protected] Figure 1. Enzyme-triggered prodrugs of carboxylic acids.

benzylation, for drugs with a carboxylic acid or hydroxyl/amino group. These prodrugs can be designed easily, and can be converted into their corresponding parent drugs with and without the help of enzymes under physiological conditions. The first prodrug strategy described involves use of drugs with a hydroxyl group. Many esters of drugs with a carboxylic acid are also known as esterase-triggered prodrugs, and could easily release the parent drugs in vivo.1,2 The anti-influenza drug, oseltamivir, is a representative ester-type prodrug. 10 As ester-type prodrugs have simple structures and good chemical stability, they can be easily designed and prepared at low cost. However, some esters cannot be cleaved by in vivo esterases, or their cleavage rates are extremely slow. Thus this strategy is limited by the chemical structures of the parent drugs. One solution is the use of enzyme-triggered prodrug with a spontaneous cleavable linker (Fig. 1), as demonstrated by pivampicillin11 (prodrug of antimicrobial ampicillin), candesartan cilexetil12 (prodrug of angiotensin II receptor antagonist, candesartan), and olmesartan medoxomil 13 (prodrug of angiotensin II receptor antagonist, olmesartan). They can be rapidly converted to their corresponding parent drugs in two steps, first hydrolysis by esterases followed by spontaneous cleavage of the linker. These prodrugs have enhanced oral-bioavailability because of their high lipophilicity. The second strategy involves modification of the hydroxyl group found in many drugs by varying functional groups. Many prodrugs have removable moieties such as phosphates,14,15 sugars, 16,17 amino acids,18,19 and organic acids20 that are covalently attached to the hydroxyl groups of their parent drugs; these prodrugs can be converted easily by enzymes such as alkaline phosphatase, sugar digesting enzymes, peptidase, and esterase, respectively. Prodrugs with a hydrophilic moiety, such as phosphates, sugars and amino acids could be used as watersoluble prodrugs, and prodrugs with a hydrophobic acyl moiety could be used to improve their oral absorption and cell membrane permeability. For example, fosamprenavir21 (Fig. 2) is the phosphate-type water-soluble prodrug of the human immunodeficiency virus type 1 (HIV-1) protease inhibitor amprenavir. Amprenavir is the representative sparingly watersoluble drug, and its formulations (soft gelatin capsule and oral solution) contain many solubilizers such as d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), polyethylene glycol (PEG 4000), and propylene glycol.22 Whereas these solubilizers often lead to unwanted side effects in clinical use, water-soluble fosamprenavir is able to reduce the number and size of its formulations compared with amprenavir, and thus improves drug bioavailability and the quality of life (QOL) of patients. Fosamprenavir was approved by the US Federal Drug Administration (FDA) in 2003, and then amprenavir was discontinued by the manufacture in 2004. Irinotecan (CPT-11, Fig. 2) is the prodrug of SN-38, an analogue of the anti-cancer agent and topoisomerase I inhibitor, camptothecin23 Phase II clinical trials of camptothecin were halted in the US owing to its low solubility and associated adverse drug reactions. However, irinotecan, which has improved solubility and side effects profiles, was approved by the US FDA in 1998. In this example, we can see how valuable prodrug strategies are, as they salvaged an otherwise shelved drug candidate. Yet the prodrug strategy for drugs with a hydroxyl group or a carboxylic acid is also constrained by the structures of their parent drugs. To overcome this issue, enzyme-triggered prodrugs with a spontaneous cleavable linker were developed. For example, propofol phosphate24 (Fig. 2) is the water-soluble prodrug of an intravenous sedative-hypnotic agent, propofol, and can be converted to the parent drug in the presence of alkaline

Figure 2. Enzyme-triggered prodrugs of drugs with a hydroxyl group.

phosphatase. However, propofol phosphate that has no linker between the phosphate ester and propofol is unsuitable for clinical use because of its slow onset and long duration of action. Hence, fospropofol (Fig. 2) was designed; its spontaneous removable linker allows for the release of the parent drug propofol via alkaline phosphatase-triggered degradation, and subsequently spontaneous cleavage of the linker25 Its disodium salt has been used clinically as the first FDA-approved watersoluble propofol prodrug. Fig. 2 shows another anti-cancer agent, a glucuronide-type prodrug with a p-hydroxybenzyl group as a spontaneous cleavable linker.26 The glucuronide bond of the prodrug can be degraded by β-glucuronidase before spontaneous cleavage of the p-hydroxybenzyl linker via 1,6-elimination reaction.24 This prodrug has improved water-solubility when compared with camptothecin, with a t1/2 value of about 20 min in the presence of 0.1 µg/mL glucuronidase (pH 7.0 phosphate buffer, 37 °C). With regards to prodrug strategies that rely on an enzyme-triggered cleavable group and a spontaneous cleavable linker, alkaline phosphatase, esterase, peptidase, and oxidation/reduction enzymes are known as the trigger-enzymes. This prodrug strategy is also applicable to drugs with an amino group, with other such enzyme-triggered cleavable linkers described later in the section on prodrugs of drugs with an amino group. Previously, we described two novel approaches to watersoluble prodrugs27-33 that allow for the release of the corresponding parent drugs with a hydroxyl group under physiological conditions without help of enzymes (Fig. 3).

Figure 3. Our two novel approaches to prodrug design for drugs with a hydroxyl group.

Because the anti-cancer agent paclitaxel is representative of this type of sparingly water-soluble compound, its injectable formulations require a detergent, such as Cremophor EL, which has been suggested to cause hypersensitivity. By focusing on the β-hydroxyethylamine side chain in the chemical structure of paclitaxel, we designed the prodrug, O-benzoyl-isopaclitaxel, in which the benzoyl group on the amino group of the paclitaxel was moved to its hydroxyl group. 30,31 This paclitaxel prodrug (Fig. 3) is stable in water as a salt, and can be rapidly converted to the parent drug via O-N intramolecular acyl migration reaction under physiological conditions (t1/2 = 15 min, pH 7.4 PBS buffer, 37°C). As this paclitaxel prodrug and paclitaxel itself are labile in acidic media such as gastric fluid, this water-soluble paclitaxel prodrug is suitable as an injectable drug. Another prodrug strategy includes the application of a cyclization reaction to a succinyl amide group.32,33 The active site of HIV-1 protease has some hydrophobic pockets; thus many potent HIV-1 protease inhibitors that are optimized for the active site have high hydrophobicity and are sparingly water soluble. Our previously reported HIV-1 protease inhibitor, KNI-727,32,33 also showed sparing water-solubility similar to amprenavir. Hence, we designed a novel water-soluble prodrug of KNI-72733-36 (Fig. 3) based on the cyclization reaction of a succinyl amide moiety. A succinyl amide structure is contained in the Asn residue of peptides and proteins, and it is well-known that the molecules that possess an Asn residue are often degraded via the cyclization of this Asn residue. As an example, a protein, intein, also called “protein intron” undergoes protein splicing. Intein has an Asn residue at the C-terminus, and the C-terminus of intein is cleaved via the cyclization of this Asn residue.37,38 We took advantage of this cyclization reaction to design novel prodrugs of HIV-1 protease inhibitors. Although the cleavage reaction of KNI-727 with a succinyl amide moiety (R = H) is very slow, the introduction of an ethylene diamine mono-amide (R = -CH2-CH2 NH2) into the succinyl moiety significantly accelerated the degradation rate (t1/2 = 12 min, pH 7.4 PBS buffer, 37°C). This prodrug was water-soluble and stable in water and acidic media such as gastric fluid, and could release its parent drug rapidly and spontaneously under physiological conditions such as gastrointestinal fluids. Lastly, prodrug formation strategies involving drugs with an amino group as shown in Figure 4 are described. Although a

portion of an amino acid or peptide residue and a long chain acyl group on an amino group on drugs can be cleaved by peptidases and esterases, respectively, the prodrug design for drugs with an amino group is constrained by the chemical structures of the parent drugs. Midodrine is the glycine amide prodrug of a vasopressor/anti-hypotensive agent, 1-(2’,5’-dimethoxyphenyl)2-aminoethanol (DMAE)39,40 that releases its parent drug DMAE via cleavage by peptidase (Fig. 4). Midodrine improved the oral absorption and duration of action of DMAE, and was approved by the US FDA in 1996; however, the US FDA proposed withdrawing their approval in 2010. Dabigatran etexilate is the prodrug of an anticoagulant agent, the direct thrombin inhibitor, dabigatran.41-44 The amidino group and carboxylic acid of dabigatran of dabigatran etexilate are modified into an alkyloxy carbonyl group (an acyl group analogue) and ethyl group, respectively, which ultimately releases its parent drug dabigatran via cleavage by esterase in vivo. Dabigatran etexilate, with its improved bioavailability, was the first oral alternative to warfarin, and earned US FDA approval in 2010. However, because an amide bond is more difficult to cleave than an ester bond, clinical use of amide-type prodrugs is actually quite rare. Therefore, many enzyme-triggered prodrugs possessing a spontaneously cleavable linker, such as p-substituted benzyloxycarbonyl group and “trimethyl lock system,” on the amino group of parent drugs have been reported. The psubstituted benzyloxycarbonyl group is cleaved via spontaneous 1,6-elimination after the enzyme-triggered reaction (Fig. 4). Prodrugs that have a phosphate ester, 45 amino acid,46 and glucuronide47,48 on the hydroxyl group at the p-position of their benzyloxycarbonyl group can release their parent drugs via cleavage by alkaline phosphatase, peptidase, and β-glucuronidase, respectively, following the spontaneous 1,6-elimination reaction. In the same way, after the p-nitro49 and p-azide50 groups on a prodrug’s benzyloxycarbonyl moiety are reduced by reduction enzymes, the parent drugs can be released via 1,6-elimination reaction. Prodrugs with a disulfide bond-mediated solubilizing moiety51 can also release their parent drugs via reduction agents following a 1,6-elimination reaction. This strategy was applied to the design of prodrugs of anti-cancer agents such as camptothecin. Because cancer cells survive under hypoxic conditions, prodrug strategy targeting reducing enzymes or substances present in the cancer cells is useful for the development of various anti-cancer agents. The “trimethyl lock

Figure 4. Enzyme-triggered prodrugs for drugs with an amino group.

system” is another reported strategy based on an amide bond cleavage reaction. The amide bond on the trimethyl lock system is fixed by three methyl groups, and can be easily cleaved by the nucleophilic attack of a phenolic hydroxyl group following lactonization (Fig. 4). Prodrugs that have a phosphate ester52 and acyl ester53 on the phenolic hydroxyl group (Fig. 4) can release their parent drugs via alkaline phosphatase and esterase, respectively, following lactonization. Prodrugs that have a

Figure 5. Our novel prodrug strategy for drugs with an amino group.

quinone moiety54 (Fig. 4) can release their parent drugs via a reduction enzyme following the lactonization of the “trimethyl lock system.” However, these prodrugs with a hydrophobic aromatic ring moiety tend to resist dissolution in water. Thus, these enzyme-triggered cleavable linkers are applicable to these prodrugs of drugs with a hydroxyl group, as described above. Recently we described a novel water-soluble prodrug strategy55 that can spontaneously release their corresponding

H2N

H N

O

O H 2N

O

NH

N

O

pH 7.4 PBS buffer

(t1/2 < 1 min)

quinine

O

N quinine prodrug 1

pH 7.4 PBS buffer

N O

O

HN HN

O

HN N H

N quinine prodrug 2 (t1/2 = 1.7 h)

Figure 6. Comparison of the cleavage rates between the guanidine-acetate and γ-aminobutyrate types of prodrugs.

parent drugs with an amino group under physiological conditions without the help of enzymes. These prodrugs with a guanidinoacyl group on their amino group are stable as a salt, and can rapidly release their parent drugs under physiological conditions. As an example, the prodrugs of the representative sparing watersoluble drugs, phenytoin and sulfathiazole, are shown in Fig. 5. Because phenytoin can be only dissolved in strongly alkaline aqueous solutions, the injectable formulations of phenytoin are prepared as aqueous solutions at pH 12, and thus often possess strong irritant properties. The phenytoin prodrug designed using our strategy had a rapid drug release rate (t1/2 = 13 min) under physiological condition (pH 7.4 PBS buffer, 37 °C). The prodrug of a sulfur drug, sulfathiazole, had a moderate drug release rate (t1/2 = 40 min) under physiological condition (pH 7.4 PBS buffer, 37 °C). The prodrugs of phenytoin and sulfathiazole appear to be suitable for injection and oral administration, respectively. Since an amide bond is never cleaved under physiological conditions without the help of enzymes, we hypothesized that the driving force of our drug release reaction was the formation of a fivemembered heterocyclic compound, and that these heterocyclic compounds are stabilized with a conjugate structure. Curiously, a γ-aminobutyl group on an amino group seems to form the same five-membered ring, but is not cleaved under physiological conditions. Therefore, in order to compare the cleavage rates between our guanidino-acyl group and γ-aminobutyl group, both types of the ester-type prodrugs of quinine possessing a hydroxyl group were synthesized (Fig. 6). Although quinine prodrug 1 with a guanidino-acetyl ester showed a rapid drug release rate (t1/2 < 1 min), quinine prodrug 2 with a γ-aminobutyl group showed a much slower drug release rate (t1/2 = 1.7 h).55 As the prodrug developed using our strategy demonstrated a t1/2 hundred-fold more rapid than that of the γ-aminobutylate-type prodrug, we concluded that the driving force of our prodrug reaction was the formation of five-membered heterocyclic compounds that were stabilized with a conjugate structure. The five-membered heterocyclic compound glycocyamidine that is commonly present in human muscle tissue has an excellent safety. Its ring-opened product, glycocyamine (guanidinoacetate), is metabolized into creatine by N-methyltransferase in the presence of S-adenosyl methionine as a methyl donor. Hence, our strategy using a guanidinoacetyl group as a removable moiety seems to be most suitable for the prodrug design. In conclusion, we have reviewed the recent progress of prodrug strategies based mainly on generally applicable modifications, including esterification, amidation, and benzylation. The design of many conventional drugs, such as levodopa and AZT, which are the metabolic precursors of more active forms, is difficult because these precursors were largely discovered by chance. Although enzyme-cleavable prodrugs, in which the drug’s carboxylic acid or hydroxyl/amino groups are directly modified into their esters or amides, can be easily

designed and prepared at low cost, they are still limited by the chemical structures of their parent drugs. Therefore, many enzyme-triggered prodrugs possessing a spontaneously cleavable linker for drugs with a carboxylic acid or a hydroxyl/amino group have been developed. We also described three novel approaches to prodrug design for drugs with a hydroxyl/amino group. These prodrugs are stable in water and can release their parent drugs under physiological conditions without the help of enzymes. These prodrug strategies in this digest paper are expected to make the development of the prodrugs more practical because they are applicable to many drugs with a carboxylic acid or hydroxyl/amino group.

Acknowledgments This study was supported in part by the Grant-in-Aid for Scientific Research from MEXT (Ministry of Education, Culture, Sports, Science, and Technology), Japan (KAKENHI No. 23590137 and No. 26460163) and a donation from Professor Emeritus Tetsuro Fujita of Kyoto University. At the time writing, we received word that Prof. Fujita had passed away on January 1, 2017. Prof. Fujita was my teacher, and was known as the inventor of a treatment agent for multiple sclerosis. I dedicate this article to Prof. Fujita.

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