Cleavage Of Prodrug Research Articles

Prodrug Strategy Extends the Use of Anti-HIV Sulfanylbenzamides for Application In Vivo.

Sulfanylbenzamide thioesters are molecules with anti-HIV activity that disrupt zinc coordination in the viral protein NCp7. These molecules are useful as topical microbicides; however, they are too unstable to be used systemically. In this article, a nitroimidazole prodrug was used to protect the sulfanylbenzamide to convey blood stability and oral bioavailability to the molecule. Studies on the molecule called nipamovir were performed to assess the rate of prodrug cleavage, antiviral activity, mechanism of metabolism, and in vivo pharmacokinetics in several different species. An efficient and inexpensive synthesis of nipamovir is also described. The results indicate that nipamovir could be further developed as a new type of drug to treat HIV infection.

Optimizing chemistry at the surface of prodrug-loaded cellulose nanofibrils with MAS-DNP

Studying the surface chemistry of functionalized cellulose nanofibrils at atomic scale is an ongoing challenge, mainly because FT-IR, NMR, XPS and RAMAN spectroscopy are limited in sensitivity or resolution. Herein, we show that dynamic nuclear polarization (DNP) enhanced 13C and 15N solid-state NMR is a uniquely suited technique to optimize the drug loading on nanocellulose using aqueous heterogenous chemistry. We compare the efficiency of two conventional coupling agents (DMTMM vs EDC/NHS) to bind a complex prodrug of ciprofloxacin designed for controlled drug release. Besides quantifying the drug grafting, we also evidence the challenge to control the concurrent prodrug adsorption and to optimize washing procedures. We notably highlight the presence of an unexpected prodrug cleavage mechanism triggered by carboxylates at the surface of the cellulose nanofibrils.

KATP Channel Prodrugs Reduce Inflammatory and Neuropathic Hypersensitivity, Morphine-Induced Hypersensitivity, and Precipitated Withdrawal in Mice.

Previous studies show ATP-sensitive potassium (KATP) channel openers can reduce hypersensitivity associated with chronic pain models in rodents, and reduce morphine tolerance. Many agonists of KATP channels are not soluble in physiologically relevant vehicles, requiring adaptation for clinical use. This study compared the antinociceptive activity of novel KATP channel targeting prodrugs, CKLP1, CKLP2, and CF3-CKLP. These prodrugs are activated by endogenous alkaline phosphatase enzymes present in the peripheral and central nervous systems. Analgesic capabilities of intrathecally injected prodrugs were tested in rodent models of spinal nerve ligation (SNL) and complete Freund's adjuvant (CFA) as models for neuropathic and inflammatory pain, respectively. CKLP1 and CKLP2 significantly increased mechanical paw withdrawal thresholds 1-2 hours after intrathecal administration in the SNL model, but all three prodrugs were able to attenuate hypersensitivity up to 7 days after CFA treatment. The reduction of opioid tolerance and opioid-induced hypersensitivity in mice treated chronically with morphine was significantly reduced in CKLP1 and CKLP2 treated animals. Prodrug cleavage was confirmed in mouse spinal cords using liquid chromatography. These studies may aid in the further development of KATP channel prodrugs for use in treatments of chronic pain, opioid tolerance, and withdrawal. SIGNIFICANCE STATEMENT: The cromakalim prodrugs, CKLP1, CKLP2, and CF3-CKLP1 reduced hypersensitivity in inflammatory and neuropathic pain models in male and female mice. CKLP1 and CKLP2 also reduced morphine-induced hypersensitivity in a mouse model of chronic morphine exposure. CKLP2 reduced jumping and rearing behaviors after naloxone-induced precipitated morphine withdrawal. Taken together, CKLP2 demonstrates the potential for development as a non-opioid analgesic drug.

Evaluating antitumor activity of Escherichia coli purine nucleoside phosphorylase against head and neck patient-derived xenografts.

Purine nucleoside phosphorylase (PNP) gene transfer represents a promising approach to treatment of head and neck malignancies. We tested recombinant adenovirus already in phase I/II clinical testing and leading-edge patient-derived xenografts (PDX) as a means to optimize this therapeutic strategy. Our experiments investigated purine base cytotoxicity, PNP enzyme activity following treatment of malignant tissue, tumor mass regression, viral receptor studies, and transduction by tropism-modified adenovirus. Replication deficient vector efficiently transduced PDX cells and mediated significant anticancer effect following treatment with fludarabine phosphate in vivo. Either 6-methylpurine or 2-fluoroadenine (toxic molecules generated by the PNP approach) ablated head and neck cancer cell proliferation. High levels of adenovirus-3 specific receptors were detected in human tumor models, and vector was evaluated that utilizes this pathway. Our studies provide the scientific foundation necessary to improve PNP prodrug cleavage and advance a new treatment for head and neck cancer.

Improving Drug Delivery While Tailoring Prodrug Activation to Modulate Cmax and Cmin by Optimization of (Carbonyl)oxyalkyl Linker-Based Prodrugs of Atazanavir.

Structure-property relationships associated with a series of (carbonyl)oxyalkyl amino acid ester prodrugs of the marketed HIV-1 protease inhibitor atazanavir (1), designed to enhance the systemic drug delivery, were examined. Compared to previously reported prodrugs, optimized candidates delivered significantly enhanced plasma exposure and trough concentration (Cmin at 24 h) of 1 in rats while revealing differentiated PK paradigms based on the kinetics of prodrug activation and drug release. Prodrugs incorporating primary amine-containing amino acid promoieties offered the benefit of rapid bioactivation that translated into low circulating levels of the prodrug while delivering a high Cmax value of 1. Interestingly, the kinetic profile of prodrug cleavage could be tailored for slower activation by structural modification of the amino terminus to either a tertiary amine or a dipeptide motif, which conferred a circulating depot of the prodrug that orchestrated a sustained release of 1 along with substantially reduced Cmax and a further enhanced Cmin.

Multicomponent Reactions (MCRs) with o-Quinone Methides.

This article presents a comprehensive overview of multicomponent reactions (MCRs) that proceed via ortho-quinone methide intermediates (o-QM) generated in the reaction medium. Examples of applications involving these highly reactive intermediates in organic synthesis and biological processes (e. g., biosynthetic pathways, prodrug cleavage and electrophilic capture of biological nucleophiles) are also described. QMs are often generated by eliminative processes of phenol derivatives or by photochemical reactions, including reversible generation in photochromic substances. This class of compounds can undergo various reaction types, including nucleophilic attack at the methide carbon, with subsequent rearomatization, and react with electron-rich dienophiles in inverse-electron demand hetero-Diels-Alder reactions. Its versatile reactivity has been explored in the context of cascade reactions for the construction of several classes of substances, including complex natural products.

Design and synthesis of an oral prodrug alalevonadifloxacin for the treatment of MRSA infection

Levonadifloxacin is a parenteral anti-MRSA benzoquinolizine antibacterial drug recently launched as, EMROK in India to treat acute bacterial skin and skin structure infections (ABSSSI) in hospitalized patients. As a step down therapy an oral form of levonadifloxacin with comparable PK/PD was needed because the levonadifloxacin exhibits very poor oral absorption. To improve the drugability in terms of oral absorption a pro-drug approach was evaluated. Structurally levonadifloxacin provides two sites amenable for ester or amide formation, a carboxyl function of benzoquinolizine pharmacophore and hydroxyl group on piperidine side chain. Several aliphatic, aromatic and amino acid esters of C-2 carboxylic acid, C-4-hydroxyl piperidine and double esters at both C-2, C-4 positions were synthesized. The cleavage of prodrugs was studied in vitro as well as in animal models to access their suitability as prodrug function. Among C-2 carboxylic ester prodrugs, daloxate (WCK 2320) showed highest cleavage in serum as well as in liver enzyme; however its stability in aqueous solution was unfavorable. In contrast, most of the esters at the hydroxyl group like propionyl ester (WCK 2305) and amino acid esters such as l-alanine (WCK 2349), l-valine (WCK 2630) were cleaved readily releasing active drug. Thus, indicating C-4-hydroxyl piperidine was amenable site for enzymatic cleavage over esters of C-2 carboxylic acid. Additionally, amino acid esters provided an opportunity to make salt, facilitating improved aqueous solubility. Methanesulfonate salt of l-alanine ester of levonadifloxacin (WCK 2349) was successfully developed and launched as oral prodrug alalevonadifloxacin (EMROK-O).

NIR-controlled morphology transformation and pulsatile drug delivery based on multifunctional phototheranostic nanoparticles for photoacoustic imaging-guided photothermal-chemotherapy

Stimuli-responsive nanoparticles are focused to promote the pathological specificity and controlled therapeutic activation in biomedicine, but the multifunctional modulation remains challenging. Herein, size and morphology switchable phototheranostic nanoparticles are developed for photoacoustic (PA) imaging-guided photothermal-chemotherapy. Multifunctional polypyrrole (PPy) nanoparticles with the template of upper critical solution temperature (UCST) polymers are designed to achieve light-controlled pulsatile drug release and concurrent activation of photothermal therapy (PTT). Wherein the UCST-featured inner core is loaded with camptothecin (CPT), the outer corona is tethered with thermo-cleavable doxorubicin (DOX) prodrug and further in-situ coated with PPy, affording the resultant CPT@DOX-UCST/PPy nanoparticles. Upon 808 nm continuous laser illumination, significant heating generated from light-absorbable PPy results in DOX prodrug cleavage and considerable size swelling (∼125-fold), which in turn promotes simultaneous dual drug release, and thus triggering the combined therapeutic activation of PTT and chemotherapy. When laser is switched off, the discontinued photothermal generation makes the nanoparticle shrink back, thereby avoiding the leakage of CPT and DOX. In vivo experiments demonstrate the favorable tumor accumulation and prolonged tumor retention (>24 h) for long-term PA imaging-guided combination therapy. Current multifunctional nanoparticles integrated with light-controlled swelling/shrinking and synergistic therapeutic activation/silence represent a promising platform for precision cancer theranostics.

Abstract A110: Hypoxia-selective DNA-PK inhibitor

Abstract Targeting tumor hypoxia continues to be a goal of translational radiation oncology owing to overwhelming preclinical and clinical validation of the importance of tumor oxygenation to radiation sensitivity. We describe a rational, structure-based drug development and characterization program for novel prodrugs that can target DNA-PK selectively within hypoxic tumor cells. The dual selectivity of these prodrugs has the potential to substantially improve the therapeutic index of radiation therapy used to treat numerous cancers. Using several biochemical, cell and novel tissue-based screening systems we explored the mechanistic and biologic activity of two new classes of DNA-PK inhibitors. Iterative improvements in molecular activity were driven by high-throughput assays utilizing both immunostaining and clonogenic survival endpoints. Kinase selectivity and in vitro ADME assays facilitated the identification of drug-like compounds with the potential for good oral bioavailability. 3D-tissue culture models helped explore tissue penetration and bystander effects and experiments analyzing the oxygen dependence of prodrug cleavage to the active DNA-PK inhibitors guided the selection of hypoxic trigger moieties. Novel parental compounds and hypoxia-activated prodrugs in two distinct chemical classes that are potent inhibitors of DNA-PK have been developed. Lead compounds exhibit high in vitro potency and good oral drug-like properties and show significant enhancement of radiation-induced cytotoxicity. In vivo experiments indicate excellent oral bioavailability with plasma T½‘s exceeding 30 minutes and significant antitumor activity against human xenografts. Citation Format: Alastair H. Kyle, Jennifer H.E. Baker, Karen H. Fryer, Judit Bana áth, Taixiang Wang, Soraya S. Porres, Sam E. Mann, George Hynd, Keith Menear, Andrew I. Minchinton. Hypoxia-selective DNA-PK inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A110.

Next-Generation Reduction Sensitive Lipid Conjugates of Tenofovir: Antiviral Activity and Mechanism of Release

The pharmacokinetic properties of tenofovir (TFV) and other charged nucleoside analogues are dramatically improved upon conjugation to a lipid prodrug. We previously prepared reduction-sensitive lipid conjugates of TFV that demonstrate superior antiviral activity compared to other lipid conjugates including the clinically approved formulation, tenofovir disoproxil fumarate (TDF). In continuation of that work, we have synthesized next-generation conjugates with reduced cytotoxicity that retain potent antiviral activity against HIV-1 and HBV with a therapeutic index >100000 for our most potent conjugate. We also show that disulfide reduction is not responsible for prodrug cleavage unless 3-exo-tet intramolecular cyclization can occur, suggesting that enzymatic hydrolysis is predominantly responsible for activity of our prodrugs in vitro.

Intramolecular Processes and Their Applications in Prodrugs Approaches- Experimental and Computational Studies

This review supplies the reader with a detailed overview on the utilization of intramolecular processes for a design and synthesis of prodrugs. It is well known that a respected number of drugs suffer from low bioavailability, toxicity, unpleasant taste and presystemic first-pass metabolism which result in drug inactivation. The classical prodrug approach in which the linkage attaching the parent drug to its non-toxic linker and cleaved by in vivo enzyme’s catalyzed reactions has proven its success in solving toxicity and bioavailability related issues. On the other hand, prodrugs based on chemical interconversion in which the prodrug releases the corresponding active parent drug via inter or intramolecular chemical process in the absence of an enzyme is considered as a better alternative approach since the prodrug cleavage is not dependent in the efficiency or quantity of the enzyme catalyzes the interconversion of the prodrug. Examples of successful prodrugs using the chemical approach via intramolecular processes such as cyclization reactions are illustrated as well. In addition, another part of this review is devoted to cover reported studies on enzyme models and their utilization for the design and synthesis of a variety of novel prodrugs. In this approach, computational calculations using DFT and MM methods were exploited and correlations between experimentally determined and computed values of the rate-limiting step in the studied intramolecular processes were utilized in the prodrugs design. Selected examples of the designed prodrugs include aza-nucleosides for the treatment of myelodysplastic syndromes, the anti-Parkinson’s agent dopamine, the anti-viral acyclovir, the anti-malarial atovaquone, and statins for lowering cholesterol levels in the blood, the antihypertensive atenolol, the antibacterial cefuroxime, the anti-bleeding tranexamic acid, the decongestant phenylephrine, and the pain killer paracetamol.

On the Existence of the Chair Conformation in Six-Membered Ring Phosphates Bearing an Aryl Group Axially Oriented at the C4 Position: Cyclic Nucleotides As Model Compounds for Cyclic Phosph(on)ate and Phosphoramide Prodrugs

A series of cyclic nucleotide analogues to HepDirect prodrugs were prepared by a three-component reaction of protected thymine, phosphoryl chloride, and 5-aryl-alpha-D-xylofuranoses derivatives. One of the cyclic nucleotides showed NMR data that suggest a predominant twisted conformation; however, in spite of having an aryl group at the C4 position within the crystal lattice, the cyclic nucleotide had a chair conformation with the aryl group axially oriented. By analyzing the unprecedented X-ray structure, it was observed that the oxygen atom from the phoshoryl group (P=O) is found in close proximity to the o-hydrogen atom of the aryl group (2.51 A), suggesting thus an attractive nonbonding electrostatic interaction, which might be the driving force that overcomes the steric diaxial interactions imposed by the aryl group. Theoretical studies (NBO) for two model compounds showed that there are indeed interactions between filled (donor) Lewis-type NBOs and empty (acceptor) non-Lewis NBOs corresponding to the nO-->sigma*(C-H) interaction. Additionally, conversion of a diastereomeric mixture of cyclic nucleotides into the more stable diastereomeric cyclic nucleotide was observed and explained by spontaneous isomerization in the phosphorinane ring. This finding supports the recently established hypothesis for the mode of action of prodrug cleavage, for which the anomeric effect plays an important role.

Discovery of a potent tubulin polymerization inhibitor: Synthesis and evaluation of water-soluble prodrugs of benzophenone analog

Prodrugs have proven to be very useful in enhancing aqueous solubility of sparingly water-soluble drugs, thereby increasing in vivo efficacy without a need of special excipients. In vitro and in vivo evaluations of a number of amino acid prodrugs of 1, a previously identified potent tubulin polymerization inhibitor and cytotoxic against various cancer cell lines led to the discovery of 3· HCl ( l-valine attached) which is highly efficacious in mouse xenografts bearing human cancer. Pharmacokinetic analysis in rats revealed that compound 1 was released immediately upon administration of 3· HCl intravenously, with rapid clearance of 3· HCl indicating the effective cleavage of prodrug. Compound 3· HCl (CKD-516) has now been progressed to phase 1 clinical trial.

Synthesis, Cleavage Profile, and Antitumor Efficacy of an Albumin‐Binding Prodrug of Methotrexate that is Cleaved by Plasmin and Cathepsin B

Cathepsin B and plasmin are intra- or extracellular proteases that are overexpressed by several solid tumors. In order to exploit both proteases as molecular targets for tumor-specific cleavage of prodrugs, an albumin-binding formulation of methotrexate was developed that incorporated the peptide sequence D-Ala-Phe-Lys as the protease substrate. Albumin is a suitable carrier for cytostatic agents due to passive accumulation in solid tumors. Synthesis was performed by coupling the peptide linker EMC-D-Ala-Phe-Lys(Boc)-Lys-OH (EMC = epsilon-maleimidocaproic acid) to the gamma-COOH group of alpha-tert-butyl protected methotrexate. After cleavage of the protective groups and purification on reverse phase HPLC, a highly water-soluble methotrexate-peptide derivative was obtained that binds rapidly and selectively to human serum albumin. The albumin-bound form of the prodrug was shown to be efficiently cleaved by cathepsin B and plasmin as well as in an ovarian carcinoma homogenate (OVCAR-3) liberating a methotrexate-lysine derivative. In an OVCAR-3 xenograft model, the prodrug at a dose of 4x15 mg/kg methotrexate equivalents demonstrated distinctly superior antitumor efficacy compared to free methotrexate at a dose of 4x100 mg/kg [T/C(%) for MTX = 69; T/C(%) for MTX prodrug = 29]. The data provide a further proof of concept for the development of albumin-binding, enzymatically cleavable prodrugs of anticancer drugs.

Design, synthesis, and characterization of a series of cytochrome P(450) 3A-activated prodrugs (HepDirect prodrugs) useful for targeting phosph(on)ate-based drugs to the liver.

A new class of phosphate and phosphonate prodrugs, called HepDirect prodrugs, is described that combines properties of rapid liver cleavage with high plasma and tissue stability to achieve increased drug levels in the liver. The prodrugs are substituted cyclic 1,3-propanyl esters designed to undergo an oxidative cleavage reaction catalyzed by a cytochrome P(450) (CYP) expressed predominantly in the liver. Reported herein is the discovery of a prodrug series containing an aryl substituent at C4 and its use for the delivery of nucleoside-based drugs to the liver. Prodrugs of 5'-monophosphates of vidarabine, lamivudine (3TC), and cytarabine as well as the phosphonic acid adefovir were shown to cleave following exposure to liver homogenates and exhibit good stability in blood and other tissues. Prodrug cleavage required the presence of the aryl group in the cis-configuration, but was relatively independent of the nucleoside and absolute stereochemistry at C4. Mechanistic studies suggested that prodrug cleavage proceeded via an initial CYP3A-catalyzed oxidation to an intermediate ring-opened monoacid, which subsequently was converted to the phosph(on)ate and an aryl vinyl ketone by a beta-elimination reaction. Studies in primary rat hepatocytes and normal rats comparing 3TC and the corresponding HepDirect prodrug demonstrated the ability of these prodrugs to effectively bypass the rate-limiting nucleoside kinase step and produce higher levels of the biologically active nucleoside triphosphate.

Designer gene therapy using an Escherichia coli purine nucleoside phosphorylase/prodrug system.

Activation of prodrugs by Escherichia coli purine nucleoside phosphorylase (PNP) provides a method for selectively killing tumor cells expressing a transfected PNP gene. This gene therapy approach requires matching a prodrug and a known enzymatic activity present only in tumor cells. The specificity of the method relies on avoiding prodrug cleavage by enzymes already present in the host cells or the intestinal flora. Using crystallographic and computer modeling methods as guides, we have redesigned E. coli PNP to cleave new prodrug substrates more efficiently than does the wild-type enzyme. In particular, the M64V PNP mutant cleaves 9-(6-deoxy-alpha-L-talofuranosyl)-6-methylpurine with a kcat/Km over 100 times greater than for native E. coli PNP. In a xenograft tumor experiment, this compound caused regression of tumors expressing the M64V PNP gene.

A new acivicin prodrug designed for tumor-Targeted delivery

Acivicin is an antitumor agent known to inhibit cell growth. A new prodrug 9b of acivicin 10 was synthesized, based on a p-hydroxybenzylcarbamate self-immolative spacer capable to release acivicin under esterase activity. The prodrug includes a maleimide-containing arm for linkage with thiol-containing macromolecules such as antibodies. This molecule is intended for the conception of bioconjugates to target an inactive acivicin precursor to tumor cells, when linked to a monoclonal antibody (mAb) which recognizes a tumor-specific antigen. Prodrug cleavage by plasmatic esterases will then restore the acivicin's activity toward tumor cells. We report here the synthesis and the in vitro characteristics of the prodrug. As expected, its inhibitory activity against the γ-glutamyl transpeptidase (γ-GT) enzyme and its cytotoxicity towards HL-60 cells were highly reduced compared to the parent drug. The chemical and plasmatic hydrolysis kinetics of the compound was studied by HPLC. The prodrug is stable, being slowly hydrolyzed in pH 7.6 buffer at 37°C with a half-life of 37 h. It is converted into an active acivicin under the effect of pig liver esterase, and its half-life in human plasma is 3 h. These results indicate this compound may be further used as a prodrug–antibody conjugate, to target acivicin to malignant cells.

Rate control of ocular pilocarpine delivery with bispilocarpic acid diesters

Ocular delivery of pilocarpine as bispilocarpic acid diester prodrugs was studied in albino rabbits using miosis as a bioassay of pilocarpine availability in the iris. Bispilocarpic acid diester fumarate eyedrops, in a dose equivalent to 0.5% pilocarpine, were administered at pH 5.0. Bispilocarpic acid diesters increased the duration of miosis and decreased the peak miotic response of pilocarpine. The time of peak miosis was delayed from 40 min to 55–135 min with the prodrugs. The duration of action was extended with seven compounds from 3 h to 4–5 h. Plateauing responses indicating sustained release of pilocarpine from the prodrug were seen in some cases. Compared with 1% pilocarpine, the prodrugs showed either increased, decreased or equal biphasic availability of pilocarpine in the iris. Neither lipophilicity nor enzymatic lability of prodrug alone could explain the miosis profile of pilocarpine. Eye irritation increased with increasing lipophilicity of the prodrugs. It appears that the ocular bioavailability of pilocarpine and its duration of action can be improved by bispilocarpic acid diesters, but in predicting their performance both lipophilicity and prodrug cleavage rate should be taken into account.

Bile salt-fatty acid mixed micelles as nasal absorption promoters. III. Effects on nasal transport and enzymatic degradation of acyclovir prodrugs.

The absorption enhancement and presystemic degradation kinetics of a homologous series of acyclovir 2'-ester prodrugs were investigated in rats using the in situ nasal perfusion technique in the presence of bile salt-fatty acid mixed micelles. In vitro incubation studies indicated that nasal perfusate containing a mixed micellar solution generated higher ester-cleaving activity than isotonic phosphate buffer washings. Inhibitor screening and substrate specificity studies demonstrated the enzyme to be most likely carboxylesterase rather than true cholinesterase. The extent of prodrug cleavage by the carboxylesterase appears to correlate well with the substrate lipophilicity for esters with linear acyl chains. On the other hand, branching of the acyl side chain significantly retards acyclovir prodrug breakdown. To estimate the nasal epithelial membrane and cytoplasmic damaging effect caused by sodium glycocholate (NaGC)-linoleic acid (15 mM:5 mM) mixed micelles, the release profiles of 5'-nucleotidase (5'-ND), lactate dehydrogenase (LDH), and carboxylesterase in the nasal perfusate were measured as a function of time. The results indicated that the activities of all three enzymes resulting from the mixed micellar solution appeared to be significantly higher than those caused by 15 mM NaGC alone. The apparent nasal absorption rate constants of acyclovir and its butyrate, valerate, pivalate, and hexanoate ester prodrugs in mixed micellar solutions containing an esterase inhibitor (1 mM phenylmethylsulfonyl fluoride) were individually calculated. Without an inhibitor, lengthening of the linear acyl side chain of the prodrug resulted in greatly accelerated degradation coupled with moderate absorption improvement. The solubilities and micellar binding constants of acyclovir prodrugs were also determined.(ABSTRACT TRUNCATED AT 250 WORDS)

The physicochemical properties, plasma enzymatic hydrolysis, and nasal absorption of acyclovir and its 2'-ester prodrugs.

A series of 2'-(O-acyl) derivatives of 9-(2-hydroxyethoxymethyl)guanine (acyclovir) was synthesized by acid anhydride esterification. Aqueous solubilities in isotonic phosphate buffer (pH 7.4), partition coefficients in 1-octanol/phosphate buffer, and hydrolysis kinetics in rat plasma were determined. The ester prodrugs showed consistent increases in lipophilicity with corresponding decreases in aqueous solubility as a function of side-chain length. The bioconversion kinetics of the prodrugs appear to depend on both the apolar and the steric nature of the acyl substituents. When perfused through the rat nasal cavity using the in situ perfusion technique, acyclovir showed no measurable loss from the perfusate. Nasal uptake of acyclovir prodrugs, on the other hand, were moderately improved. Furthermore, the extent of nasal absorption appears to depend on the lipophilicity of the prodrugs in the descending order hexanoate > valerate > pivalate > butyrate. Simultaneous prodrug cleavage by nasal carboxylesterase was also noted in the case of hexanoate.