Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic.
J Med Chem. 2010 Oct 14;53(19):6825-37. doi: 10.1021/jm901828c.
9-(S)-[3-Hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine (HPMPDAP) and its cyclic form were selected for further evaluation as potential drug candidates against poxvirus infections. To increase bioavailability of these compounds, synthesis of their structurally diverse ester prodrugs was carried out: alkoxyalkyl (hexadecyloxypropyl, octadecyloxyethyl, hexadecyloxyethyl), pivaloyloxymethyl (POM), 2,2,2-trifluoroethyl, butylsalicylyl, and prodrugs based on peptidomimetics. Most HPMPDAP prodrugs were synthesized in the form of monoesters as well as the corresponding cyclic phosphonate esters. The activity was evaluated not only against vaccinia virus but also against different herpes viruses. The most potent and active prodrugs against vaccinia virus were the alkoxyalkyl ester derivatives of HPMPDAP, with 50% effective concentrations 400-600-fold lower than those of the parent compound. Prodrugs based on peptidomimetics, the 2,2,2-trifluoroethyl, the POM, and the butylsalicylyl derivatives, were able to inhibit vaccinia virus replication at 50% effective concentrations that were equivalent or ∼10-fold lower than those observed for the parent compounds.
9-(S)-[3-羟基-2-(膦酸甲酯基)丙基]-2,6-二氨基嘌呤（HPMPDAP）及其环状形式被选为进一步评估针对痘病毒感染的潜在药物候选物。为了提高这些化合物的生物利用度，对其结构多样的酯前药进行了合成：烷氧基烷基（十六烷氧基丙基、十八烷氧基乙基、十六烷氧基乙基）、特戊酰氧甲基（POM）、2,2,2-三氟乙基、丁基水杨酰基和基于肽模拟物的前药。大多数 HPMPDAP 前药以单酯以及相应的环状膦酸酯的形式合成。不仅评估了对痘病毒的活性，还评估了对不同疱疹病毒的活性。针对痘病毒最有效和最活跃的前药是 HPMPDAP 的烷氧基烷基酯衍生物，其 50%有效浓度比母体化合物低 400-600 倍。基于肽模拟物、2,2,2-三氟乙基、POM 和丁基水杨酰基的前药能够抑制痘病毒复制，其 50%有效浓度与母体化合物相当或低 10 倍。
