Amidate Prodrugs of Cyclic 9-(S)-[3-Hydroxy-2-(phosphonomethoxy)propyl]adenine with Potent Anti-Herpesvirus Activity,ACS Medicinal Chemistry Letters

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Amidate Prodrugs of Cyclic 9-(S)-[3-Hydroxy-2-(phosphonomethoxy)propyl]adenine with Potent Anti-Herpesvirus Activity
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-03-16 00:00:00 , DOI: 10.1021/acsmedchemlett.8b00079
Min Luo ₁ , Elisabetta Groaz ₁ , Steven De Jonghe ₂ , Robert Snoeck ₂ , Graciela Andrei ₂ , Piet Herdewijn ₁

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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.

中文翻译：

环状9-（S）-[3-羟基-2-（膦酰基甲氧基）丙基]腺嘌呤具有抗疱疹病毒活性的酰胺化物前药

合成了一系列具有不同氨基酸基序的环状9- [3-羟基-2-（膦酰基甲氧基）丙基]腺嘌呤（cHPMPA）的酰胺化物前药。衍生自（S）-cHPMPA的所有磷酸亚酰胺盐均对疱疹病毒表现出广谱活性，其EC ₅₀值在低纳摩尔范围内。（S）-HPMPA的膦酰二氨基酸盐前药也表现出显着的有效抗病毒活性。此外，（的亮氨酸酯前药小号）-cHPMPA和phosphonobisamidate缬氨酸酯前药（小号）-HPMPA在人体血浆中被证明是稳定的。这些数据保证了cHPMPA前药的进一步开发，特别是针对人类巨细胞病毒（HCMV）的开发，为此迫切需要在移植受体中进行治疗。

更新日期：2018-03-16

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