Development of New Drugs for Treatment of Human Cytomegalovirus

Reist, Elmer

Abstract

We have found that the preparation of an isosteric phosphonate analog of ganciclovir (DHPG) phosphate (SR 3745) results in a compound that has highly selective antiviral activity against cytomegalovirus (CMV) in vitro, with minimal cytotoxicity. It is also highly active in vivo against murine CMV (MCMV) and has low toxicity. Not surprisingly, its oral bioavailability is quite low. One objective of this research is to prepare analogs of SR 3745 that might be expected to have improved oral bioavailability. Our approach will be to cover up some or all the functional groups of SR 3745 with groups that can be removed enzymatically after absorption through the digestive tract. Decreasing the polarity of the molecule by ester groups or ethers should accomplish this aim. Among the analogs of SR 3745 that we will examine for prodrug development are esters of the phosphonic acid moiety using assorted alkyl or aryl groups. The hydroxyl function of SR 3745 can be converted to an ether (e.g., isopropyl, benzyl, silyl) or ester derived from assorted carboxylic or amino acids. The functionality of the guanine moiety at C-6 can also be modified by preparing 6-deoxy-6-alkoxy or 6-aminopurine derivatives. Modifications of these types have been used in other nucleoside series to improve bioavailability. Prepared compounds will be evaluated for oral bioavailability in Project 3 of this program. A second goal of this program will be to prepare radiolabeled (14C and 3H) derivatives of active compounds (e.g., SR 3745) as needed for mechanism studies that are under way in Project 3 or this program.