Review of research leading to new anti-herpesvirus agents in clinical development: Valaciclovir hydrochloride (256u, the L-valyl ester of acyclovir) and 882c, a specific agent for varicella zoster virus

Abstract

Research leading to the new anti-herpesvirus compounds discussed here has come from three approaches. The first approach was directed towards improving the bioavailability of acyclovir by examining the potential of a variety of prodrugs, leading to the new compound valaciclovir hydrochloride. The second approach was to examine a large number of 5-substituted pyrimidines for activity against those viruses which were not as potently inhibited by acyclovir as are herpes simplex viruses, i.e., varicella zoster virus (VZV) and human cytomegalovirus (HCMV). This research led to the new chemical entity 882C for VZV. A third approach has been to examine drug combinations with acyclovir. This research led to the compound 348U, an inhibitor of herpes simplex virus ribonucleotide reductase which acts synergistically in combination with acyclovir. This manuscript will focus on the first two approaches leading to new compounds valaciclovir hydrochloride and 882C since Dr. Safrin details such background for 348U/acyclovir. Attempts to improve the bioavailability of acyclovir began a decade ago. Early prodrugs were compounds with alterations in the 6-substituent of the purine ring of acyclovir. The 6-amino congener required the cellular enzyme adenosine deaminase for conversion to acyclovir and the 6-deoxycongener was dependent on cellular xanthine oxidase for conversion. Neither of these prodrugs had a chronic toxicity profile in laboratory animals as good as acyclovir. Efforts were directed towards simpler esters and 18 amino acid esters were made. The pharmacokinetic profile of each prodrug was determined in rats by measuring the recovery of acyclovir in urine after oral dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Valacyclovir for the prevention of cytomegalovirus infection after allogeneic stem cell transplantation: a single institution retrospective cohort analysis

“…Serum levels and area under the curve (AUC) are comparable to those achieved with intravenous acyclovir. [13][14][15] Recent prospective randomized studies using valacyclovir for the prophylactic treatment of CMV infection have shown safety and efficacy in patients with renal transplants and AIDS. [16][17][18][19] However, the benefit of this approach for CMV prophylaxis in SCT recipients has not been reported.…”

Vaccines and Antiviral Drugs for Diseases Associated with the Epstein-Barr Virus

“…70 Nevertheless, efficiencies of these compounds as inhibitors of EBV are limited. To improve bioavailability, the orally available prodrugs valaciclovir (VACV), 71 valganciclovir (VGC; the valine ester of GCV) 72 and famciclovir (FCV) 73 have been introduced in the mid-1990s. VACV, the L-valyl ester of ACV, is rapidly and almost completely converted to ACV in vivo, as well as provided three to five times increase in ACV bioavailability.…”

Epstein-Barr Virus-Associated Classical Hodgkin Lymphoma and Its Therapeutic Strategies

“…The fi rst group includes acyclic nucleoside/nucleotide analogues and pyrophosphate analogues, the target of which is the EBV DNA polymerase. Despite their effi cient inhibition of the viral polymerase in vitro in tissue culture experiments, they have displayed limitations by toxic side effects, poor oral bioavailability, and emergence of drug-resistant virus strains in in vivo treatment (Pagano et al, 1983;Purifoy et al, 1993). Recently, through further searching for new therapeutic compounds with the enhanced specifi city in their antiviral action, a second group demonstrating unique modes of action has become available, which contains compounds of a mixed nature with divergent structures.…”