Department of Medicine, Division of Infectious Disease, University of California, San Diego, La Jolla, CA 92093-0676, USA.
Bioorg Med Chem. 2011 May 1;19(9):2950-8. doi: 10.1016/j.bmc.2011.03.034. Epub 2011 Mar 23.
Alkoxyalkyl esters of cidofovir (CDV) are orally active agents which inhibit the replication of a variety of double stranded DNA (dsDNA) viruses including variola, vaccinia, ectromelia, herpes simplex virus, cytomegalovirus, adenovirus and others. One of these compounds, hexadecyloxypropyl-CDV (HDP-CDV, CMX001) is in clinical development for prevention and treatment of poxvirus infection, vaccination complications, and for infections caused by cytomegalovirus, adenovirus, herpesviruses and other dsDNA viruses. This class of lipid analogs is potentially prone to undergo omega oxidation of the alkyl moiety which can lead to a short chain carboxylic acid lacking antiviral activity. To address this issue, we synthesized a series of alkoxyalkyl or alkyl glycerol esters of CDV and (S)-HPMPA having modifications in the structure of the alkyl residue. Antiviral activity was assessed in cells infected with vaccinia, cowpox or ectromelia viruses. Metabolic stability was determined in S9 membrane fractions from rat, guinea pig, monkey and human liver. All compounds had substantial antiviral activity in cells infected with vaccinia, cowpox or ectromelia. Metabolic stability was lowest in monkey liver S9 incubations where rapid disappearance of HDP-CDV and HDP-(S)-HPMPA was noted. Metabolic stability in monkey preparations increased substantially when a ω-1 methyl group (15-methyl-HDP-CDV) or a terminal cyclopropyl residue (14-cyclopropyl-tetradecyloxypropyl-CDV) was present in the alkyl chain. The most stable compound was 1-O-octadecyl-2-O-benzyl-sn-glycero-3-CDV (ODBG-CDV) which was not metabolized extensively by monkey liver S9. In rat, guinea pig or human liver S9 incubations, most of the modified antiviral compounds were considerably more stable.
西多福韦（CDV）的烷氧基烷酯是具有口服活性的化合物，可抑制多种双链 DNA（dsDNA）病毒的复制，包括天花、牛痘、马痘、单纯疱疹病毒、巨细胞病毒、腺病毒等。其中一种化合物，十六烷氧基丙基-CDV（HDP-CDV，CMX001）正在临床开发中，用于预防和治疗痘病毒感染、疫苗接种并发症，以及巨细胞病毒、腺病毒、疱疹病毒和其他 dsDNA 病毒引起的感染。这类脂质类似物容易发生烷基部分的ω氧化，导致失去抗病毒活性的短链羧酸。为了解决这个问题，我们合成了一系列烷氧基烷或烷基甘油酯的 CDV 和（S）-HPMPA，其烷基残基的结构有所修饰。在感染牛痘、牛痘或马痘病毒的细胞中评估了抗病毒活性。在来自大鼠、豚鼠、猴子和人肝脏的 S9 膜部分中测定了代谢稳定性。所有化合物在感染牛痘、牛痘或马痘的细胞中均具有显著的抗病毒活性。在猴子肝脏 S9 孵育中，HDP-CDV 和 HDP-（S）-HPMPA 的快速消失导致代谢稳定性最低。当烷基链中存在 ω-1 甲基（15-甲基-HDP-CDV）或末端环丙基残基（14-环丙基-十四烷氧基丙基-CDV）时，猴子制剂中的代谢稳定性会大大增加。最稳定的化合物是 1-O-十八烷基-2-O-苄基-sn-甘油-3-CDV（ODBG-CDV），它不会被猴子肝脏 S9 广泛代谢。在大鼠、豚鼠或人肝脏 S9 孵育中，大多数修饰的抗病毒化合物都更稳定。
