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Amidate Prodrugs of Cyclic 9-(S)-[3-Hydroxy-2-(phosphonomethoxy)propyl]adenine with Potent Anti-Herpesvirus Activity. 2018

Min Luo, and Elisabetta Groaz, and Steven De Jonghe, and Robert Snoeck, and Graciela Andrei, and Piet Herdewijn
Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.

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 (S)-cHPMPA displayed a broad spectrum activity against herpesviruses with EC50 values in the low nanomolar range. A phosphonobisamidate prodrug of (S)-HPMPA also exhibited a remarkably potent antiviral activity. In addition, the leucine ester prodrug of (S)-cHPMPA and phosphonobisamidate valine ester prodrug of (S)-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.

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