Of a series of nucleoside analogues synthesised, 9-(2-hydroxyethoxymethyl) guanine was found to have marked antiviral activity in animal models of herpes virus infections, associated with very low toxicity.

A guanine derivative with an acyclic side chain, 2-hydroxyethoxymethyl, at position 9 has potent antiviral activity [dose for 50% inhibition (ED50) = 0.1 ,uM] against herpes simplex virus type 1. This acyclic nucleoside analog, termed acycloguanosine, is converted to a monophosphate by a virusspecified pyrimidine deoxynucleoside (thymidine) kinase and is subsequently converted to acycloguanosine di-and triphosphates. In the uninfected host cell (Vero) these phosphorylations of acycloguanosine occur to a very limited extent. Acycloguanosine triphosphate inhibits herpes simplex virus DNA polymerase (DNA nucleotidyltransferase) 10-30 times more effectively than cellular (HeLa S3) DNA polymerase. These factors contribute to the drug's selectivity; inhibition of growth of the host cell requires a 3000-fold greater concentration of drug than does the inhibition of viral multiplication. There is, moreover, the strong possibility of chain termination of the viral DNA by incorporation of acycloguanosine.The identity of the kinase that phosphorylates acycloguanosine was determined after separation of the cellular and virus-specified thymidine kinase activities by affinity chromatography, by reversal studies with thymidine, and by the lack of monophosphate formation in a temperature-sensitive, thymidine kinase-deficient mutant of the KOS strain of herpes simplex virus type 1 (tsAl).

The pharmacokinetics and safety of the L-valyl ester pro-drug of acyclovir, valaciclovir (256U87), were investigated in two phase I, placebo-controlled trials in normal volunteers. These included a single-dose study with doses from 100 to 1000 mg (single cohort) and a multiple-dose investigation with doses from 250 to 2000 mg (five separate cohorts). In each cohort, eight subjects received valaciclovir and four subjects received placebo. Pharmacokinetic findings for valaciclovir and acyclovir were consistent in the two studies. Valaciclovir was rapidly and extensively converted to acyclovir, resulting in significantly greater acyclovir bioavailability (approximately threefold to fivefold) compared with that historically observed with high-dose (800 mg) oral acyclovir. At the higher valaciclovir doses, acyclovir maximum concentration and daily area under the concentration-time curve approximated those obtained with intravenous acyclovir. The favorable safety profile and enhanced acyclovir bioavailability from valaciclovir administration has prompted additional clinical evaluations for zoster and herpes simplex virus treatment, as well as cytomegalovirus suppression in immunocompromised patients.

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SummaryEighteen amino acid esters of the antiherpetic drug, acyclovir, were synthesized as potential prodrugs for oral administration. The esters were examined for in vitro antiviral activity against herpes simplex virus Type 1 (HSV-1). They were found to have less potency than the parent compound. Their efficiencies as prodrugs were evaluated in rats by measuring the urinary recovery of acyclovir. Ten prodrugs produced greater amounts of the parent drug in the urine. The L-amino acid esters were better prodrugs than the corresponding D-or D,L-isomers, suggesting the involvement of a stereoselective transporter. The L-valyl ester, 256U87, was the best prodrug. Sixty three per cent of its administered dose was excreted as acyclovir in the urine, a considerable improvement over acyclovir itself, for which this value was 19%. Since 256U87 was stable in aqueous solutions, its conversion to acyclovir in vivo was probably enzyme catalyzed. This L-valyl ester prodrug of acyclovir is now undergoing clinical evaluation.

The pharmacokinetics of the antiviral drug 9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl]guanine (DHPG) were examined in six patients receiving 2.5 or 5.0 mg/kg every 8 or 12 hours for human cytomegalovirus (HCMV) pneumonitis or retinitis. Biexponential decay with a mean distribution t1/2 of 0.23 hours and terminal t1/2 of 2.53 hours was observed. Total clearance correlated well with and exceeded creatinine clearance by a factor of 2.4. Mean volume of the central compartment was 15.26 L/1.73 m2 and the volume of distribution at steady state was 32.8 L/1.73 m2. Peak (model predicted) and trough plasma concentrations were 4.75 to 6.20 micrograms/ml and less than 0.25 to 0.63 microgram/ml, respectively, in patients receiving 2.5 mg/kg. Peak concentrations are well above those needed to inhibit HCMV at the 50% level (ID50) and troughs are near this ID50. Cerebrospinal fluid concentrations of DHPG indicate a penetration of 24% to 67%. No accumulation of DHPG was apparent in these patients. However, dosage reduction is necessary in renal insufficiency. Neutropenia occurred in one patient. The plasma concentration profile of DHPG suggests potential beneficial activity against HCMV.

Acyclovir {9-[(2-hydroxyethoxy)methyllguanine} is an acyclic guanine nucleoside analogue that is widely used clinically as an antiherpetic agent. Its limited absorption in humans after oral administration prompted the search for prodrugs. A congener, referred to as 6-deoxyacyclovir {2-amino-9-[(2-hydroxyethoxy)methyl]-9H-purine}, was synthesized and found to be 18 times more water soluble than was acyclovir. Surprisingly, this congener was readily oxidized to acyclovir by xanthine oxidase (EC 1.2.3.2). It was also oxidized by aldehyde oxidase (EC 1.2.3.1) largely to 8-hydroxy-6-deoxyacyclovir {2-amino-8-hydroxy-9-[(2-hydroxyethoxy)methyl]-9H-purine} and then to 8-hydroxyacyclovir {2-amino-6,8-dihydroxy-9[(2-hydroxyethoxy)methylj-9H-purine}. 6-Deoxyacyclovir and the major products of its oxidation by aldehyde oxidase lacked appreciable activity against herpes simplex type I in vitro. On the basis of these results, it was apparent that the success of 6-deoxyacyclovir as a prodrug in vivo would depend upon how well its desired activation by xanthine oxidase competed with the nonactivating oxidations by aldehyde oxidase.In rats dosed orally with 6-deoxyacyclovir, absorption was extensive and the major urinary metabolite was acyclovir. In two human volunteers, urinary excretions of acyclovir were 5-6 times greater than those typically observed after administration of equivalent doses of acyclovir itself. The areas under the plasma concentration-time curves for acyclovir were also 5-6 times greater. Plasma levels of acyclovir peaked soon after ingestion of the prodrug, indicating rapid absorption and metabolic conversion. These results suggested that 6-deoxyacyclovir might have clinical usefulness as a prodrug of acyclovir suitable for oral administration.Acyclovir {9-[(2-hydroxyethoxy)methylJguanine; Zovirax} is a clinically useful antiherpetic agent (1, 2). Intravenous (3, 4), oral (5), or topical (6, 7) administration provides-effective therapy. Only 15-20% of the dose is typically absorbed in humans after oral administration (8). This degree of absorption is adequate for efficacy against herpes simplex infections (5). However, greater absorption might be important in therapy against less sensitive viruses such as varicella-zoster virus (9). The clinical experience to date clearly indicates that although acyclovir represents a major therapeutic advance in the treatment of herpetic infections, a means of enhancing gastrointestinal absorption would significantly extend its usefulness.Considerable effort has been expended in attempts to find a prodrug that is well absorbed after oral administration and then converted to acyclovir. Esterification of the hydroxyl group of the (2-hydroxyethoxy)methyl moiety of acyclovir has been an approach taken by two separate laboratories (10,11). Unfortunately, those esters that have been tested showed no significant improvement in absorption after oral dosing (unpublished results).The 6-deoxy-6-amino congener of acyclovir {2,6-diamino-9-[(2-hydroxyethoxy)methyl]-9H-purine} (...