REVIEW OF RESEARCH LEADING TO NEW ANTI-HERPESVIRUS AGENTS IN CLINICALDEVELOPMENT - VALACICLOVIR HYDROCHLORIDE (256U, THE L-VALYL ESTER OF ACYCLOVIR) AND 882C, A SPECIFIC AGENT FOR VARICELLA-ZOSTER VIRUS

Research leading to the new anti-herpesvirus compounds discussed here has come from three approaches. The first approach was directed toward s improving the bioavailability of acyclovir by examining the potentia l of a variety of prodrugs, leading to the new compound valaciclovir h ydrochloride. The second approach was to examine a large number of 5-s ubstituted pyrimidines for activity against those viruses which were n ot as potently inhibited by acyclovir as are herpes simplex viruses, i .e., varicella zoster virus (VZV) and human cytomegalovirus (HCMV). Th is research led to the new chemical entity 882C for VZV. A third appro ach has been to examine drug combinations with acyclovir. This researc h led to the compound 348U, an inhibitor of herpes simplex virus ribon ucleotide reductase which acts synergistically in combination with acy clovir. 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 b ioavailability of acyclovir began a decade ago. Early prodrugs were co mpounds with alterations in the 6-substituent of the purine ring of ac yclovir. The 6-amino congener required the cellular enzyme adenosine d eaminase for conversion to acyclovir and the 6-deoxycongener was depen dent on cellular xanthine oxidase for conversion. Neither of these pro drugs had a chronic toxicity profile in laboratory animals as good as acyclovir. Efforts were directed towards simpler esters and 18 amino a cid esters were made. The pharmacokinetic profile of each prodrug was determined in rats by measuring the recovery of acyclovir in urine aft er oral dosing. The L-valyl ester, valaciclovir hydrochloride, was the best prodrug with 63% of the oral dose excreted as acyclovir in the u rine, a 200-400% improvement on acyclovir lone. An acceptable preclini cal profile has resulted in full-scale clinical evaluation of valacicl ovir hydrochloride. Valaciclovir hydrochloride has the potential for s uperior 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 deoxypyr imidine nucleosides for antiviral activity against HCMV and VZV led to the discovery of the potent, specific VZV compound 882C. An initial l ead compound, 5-ethynyl-2'-deoxyuridine showed potent HCMV and VZV act ivity but with unacceptable cell toxicity. Synthesis of about 80 analo gues resulted in three with potent, specific anti-VZV activity, of whi ch 882C was the best by a number of criteria. 882C demonstrates potent and highly specific anti-VZV activity without significant activity ag ainst HSV or HCMV. In addition, 882C is not cytotoxic at the highest c oncentrations tested (500 muM). Specificity is achieved since 882C is converted to the 5'-monophosphate by VZV thymidine kinase but not by c ellular cytosol thymidine kinase. Furthermore, the monophosphate is sp ecifically converted to the diphosphate by the thymidylate kinase acti vity 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 in hibitor of the VZV-specific DNA polymerase and this inhibition is prob ably the major mechanism of the antiviral activity. The intrinsic pote ncy of 882C for VZV (seven times greater than acyclovir) as well as th e pharmacokinetic profile of 882C in man makes the compound an extreme ly promising new chemical entity for the treatment of varicella zoster virus infections. (C) 1993 Wiley-Liss, Inc.