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• W2072786944 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. The L-valyl ester, valaciclovir valaciclovir hydrochloride, was the best prodrug with 63% of the oral dose excreted as acyclovir in the urine, a 200–400% improvement on acyclovir alone. An acceptable preclinical profile has resulted in full-scale clinical evaluation of valaciclovir hydrochloride. Valaciclovir hydrochloride has the potential for superior efficacy and greater convenience in the management of HSV and VZV infections and the prophylaxis of HCMV infections, with the known safety profile of acyclovir as background. Research examining deoxypyrimidine nucleosides for antiviral activity against HCMV and VZV led to the discovery of the potent, specific VZV compound 882C. An initial lead compound, 5-ethynyl-2′-deoxyuridine showed potent HCMV and VZV activity but with unacceptable cell toxicity. Synthesis of about 80 analogues resulted in three with potent, specific anti-VZV activity, of which 882C was the best by a number of criteria. 882C demonstrates potent and highly specific anti-VZV activity without significant activity against HSV or HCMV. In addition, 882C is not cytotoxic at the highest concentrations tested (500 μM). Specificity is achieved since 882C is converted to the 5′-monophosphate by VZV thymidine kinase but not by cellular cytosol thymidine kinase. Furthermore, the monophosphate is specifically converted to the diphosphate by the thymidylate kinase activity of the VZV thymidine kinase. The lack of activity of 882C for HSV correlates with the inability of the HSV thymidine kinase to use 882C monophosphate as a substrate. The triphosphate of 882C is a potent inhibitor of the VZV-specific DNA polymerase and this inhibition is probably the major mechanism of the antiviral activity. The intrinsic potency of 882C for VZV (seven times greater than acyclovir) as well as the pharmacokinetic profile of 882C in man makes the compound an extremely promising new chemical entity for the treatment of varicella zoster virus infections." @default.
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• W2072786944 title "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" @default.
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• W2072786944 doi "https://doi.org/10.1002/jmv.1890410527" @default.
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