Martin J A, Thomas G J, Merrett J H, Lambert R W, Bushnell D J, Dunsdon S J, Freeman A C, Hopkins R A, Johns I R, Keech E, Simmonite H, Kai-In P W, Holland M
Department of Medicinal Chemistry, Roche Discovery Welwyn, Herts, UK.
Antivir Chem Chemother. 1998 Jan;9(1):1-8.
The rational design and synthesis of nucleotide analogues as inhibitors of herpes simplex virus (HSV) thymidine kinase is described. Starting from thymidine, product analogues which included phosphates, phosphonates, sulphonates, sulphonamides and carboxamides were prepared. The carboxamide series showed good structure-activity relationships and afforded a lead structure which inhibited the HSV-2 enzyme in the low micromolar range. Replacing the 5-methyl group in thymidine by ethyl enhanced the potency of the lead structure 10-fold. Further optimization of the carboxamide moiety afforded inhibitors active in the sub-nanomolar range and finally the introduction of a 2'-beta-fluoro substituent improved the potency a further twofold. The low water solubility of the most potent inhibitor was overcome by conversion to the 3'-valyl ester, which had good oral bioavailability and showed activity by the oral route in murine models of infection.
描述了作为单纯疱疹病毒（HSV）胸苷激酶抑制剂的核苷酸类似物的合理设计与合成。从胸苷开始，制备了包括磷酸盐、膦酸盐、磺酸盐、磺酰胺和羧酰胺的产物类似物。羧酰胺系列显示出良好的构效关系，并提供了一种先导结构，该先导结构在低微摩尔范围内抑制HSV-2酶。用乙基取代胸苷中的5-甲基可使先导结构的效力提高10倍。对羧酰胺部分的进一步优化得到了在亚纳摩尔范围内有活性的抑制剂，最后引入2'-β-氟取代基使效力又提高了两倍。通过转化为3'-缬氨酸酯克服了最有效抑制剂的低水溶性，该酯具有良好的口服生物利用度，并在小鼠感染模型中通过口服途径显示出活性。
