Luo Min, Groaz Elisabetta, De Jonghe Steven, Snoeck Robert, Andrei Graciela, Herdewijn Piet
Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Herestraat 49 bus 1043, 3000 Leuven, Belgium.
ACS Med Chem Lett. 2018 Mar 16;9(4):381-385. doi: 10.1021/acsmedchemlett.8b00079. eCollection 2018 Apr 12.
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.
合成了一系列具有不同氨基酸基序的环状9-[3-羟基-2-(膦酰甲氧基)丙基]腺嘌呤（cHPMPA）的酰胺前药。所有源自(-)-cHPMPA的膦酰胺对疱疹病毒均表现出广谱活性，其半数有效浓度（EC）值处于低纳摩尔范围。(-)-HPMPA的膦双酰胺前药也表现出显著的强效抗病毒活性。此外，(-)-cHPMPA的亮氨酸酯前药和(-)-HPMPA的膦双酰胺缬氨酸酯前药在人血浆中被证明是稳定的。这些数据表明cHPMPA前药值得进一步研发，特别是针对人巨细胞病毒（HCMV），在移植受者中对其治疗有很高的需求。
