Beadle James R, Wan William B, Ciesla Stephanie L, Keith Kathy A, Hartline Caroll, Kern Earl R, Hostetler Karl Y
Department of Medicine, VA San Diego Healthcare System and the University of California, San Diego, La Jolla, California 92093-0676, USA.
J Med Chem. 2006 Mar 23;49(6):2010-5. doi: 10.1021/jm050473m.
9-(S)-(3-Hydroxy-2-phosphonomethoxypropyl)adenine [(S)-HPMPA] was one of the first acyclic nucleoside phosphonates described and has been reported to have good antiviral activity against most double-stranded DNA viruses, including the herpes group viruses and the orthopoxviruses. However, (S)-HPMPA is not orally bioavailable and has not been developed for clinical use. We have prepared orally bioavailable lipid esters of (S)-HPMPA and report their synthesis and antiviral evaluation against cytomegalovirus and orthopoxviruses. These esters were evaluated in vitro in cells infected with human cytomegalovirus (HCMV), murine cytomegalovirus (MCMV), vaccinia (VV), and cowpox viruses (CV). The most active compound, oleyloxyethyl-(S)-HPMPA, was found to have EC50 value of 0.003 microM against HCMV vs 1.4 microM for unmodified HPMPA. In cells infected with VV and CV, octadecyloxyethyl-(S)-HPMPA had EC50 values of 0.01-0.02 microM versus 2.7-4.0 microM for unmodified HPMPA. When compared with the alkoxyalkyl esters of cidofovir, the corresponding alkoxyalkyl esters of (S)-HPMPA were equally active against HCMV and MCMV but were 15-20-fold more active against VV and CV in vitro. The alkoxyalkyl esters of (S)-HPMPA are promising new compounds worthy of further investigation for treatment of infections caused by herpes viruses and orthopoxviruses.
9-(S)-(3-羟基-2-膦酰甲氧基丙基)腺嘌呤[(S)-HPMPA]是最早被描述的无环核苷膦酸盐之一，据报道它对大多数双链DNA病毒具有良好的抗病毒活性，包括疱疹病毒组和正痘病毒。然而，(S)-HPMPA口服生物利用度不佳，尚未开发用于临床。我们制备了(S)-HPMPA的口服生物利用度良好的脂质酯，并报告了它们的合成以及对巨细胞病毒和正痘病毒的抗病毒评估。这些酯在感染人巨细胞病毒(HCMV)、鼠巨细胞病毒(MCMV)、痘苗病毒(VV)和牛痘病毒(CV)的细胞中进行了体外评估。发现活性最高的化合物油氧基乙基-(S)-HPMPA对HCMV的EC50值为0.003微摩尔，而未修饰的HPMPA为1.4微摩尔。在感染VV和CV的细胞中，十八烷氧基乙基-(S)-HPMPA的EC50值为0.01 - 0.02微摩尔，而未修饰的HPMPA为2.7 - 4.0微摩尔。与西多福韦的烷氧基烷基酯相比，(S)-HPMPA的相应烷氧基烷基酯对HCMV和MCMV的活性相当，但在体外对VV和CV的活性高15 - 20倍。(S)-HPMPA的烷氧基烷基酯是有前景的新化合物，值得进一步研究用于治疗由疱疹病毒和正痘病毒引起的感染。
