Amidate prodrugs of cyclic 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine with potent anti-herpesvirus activity

A series of amidate prodrugs of cyclic 9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (cHPMPA) featuring different amino acid motifs were synthesized. All phosphonamidates derived from ()-cHPMPA displayed a broad spectrum activity against herpesviruses with EC values in the low nanomolar range. A phosphonobisamidate prodrug of ()-HPMPA also exhibited a remarkably potent antiviral activity. In addition, the leucine ester prodrug of ()-cHPMPA and phosphonobisamidate valine ester prodrug of ()-HPMPA proved stable in human plasma. These data warrant further development of cHPMPA prodrugs, especially against human cytomegalovirus (HCMV), for which there is a high need for treatment in transplant recipients.status: publishe