(S)-1-(3-Hydroxy-2-(phosphonylmethoxy)propyl)cytosine (HPMPC): A Potent Antiherpesvirus Agent

Abstract

(S)-1-(3-Hydroxy-2-(phosphonylmethoxy)propyl)cytosine (HPMPC; 1, fig. 1, left) has been identified from a series of phosphonate nucleotide analogues as having the greatest therapeutic index against lethal herpes simplex virus (HSV) infections in mice (1, 2). The prototype compound of the series is the adenine analogue 2 (HPMPA; 2, fig. 1, right), which was first described by De Clercq et al. in 1986 as a broad-spectrum antiviral agent (3). HPMPA was shown to have a mechanism of action that involves, at least in part, two intracellular phosphorylations to give a diphosphate, which then selectively inhibits the viral polymerase. Since the discovery of HPMPA, additional studies have shown that many related phosphonylmethoxy nucleotide analogues have broad-spectrum in vitro activity (4, 5). Of this class of nucleotide analogues, HPMPC has been described as having the best in vitro therapeutic index against cytomegalovirus (CMV) (2, 6).