Kim C U, Misco P F, Luh B Y, Hitchcock M J, Ghazzouli I, Martin J C
Bristol-Myers Squibb Company, Pharmaceutical Research Institute, Wallingford, Connecticut 06492.
J Med Chem. 1991 Jul;34(7):2286-94. doi: 10.1021/jm00111a052.
Novel phosphonate isosteres of acyclovir (ACV) and ganciclovir (DHPG) monophosphates were found to be potent and selective antiherpesvirus agents. In the series of phosphonate analogues of ACV monophosphate, only the guanine analogue 20 exhibited activity against herpesviruses, similar to the structure-activity relationship observed for base modification of ACV analogues. The phosphonate isostere of ACV monophosphate (20) was more effective than ACV in the HSV-1 infected mouse model. The 3'-carba analogues of 9-[3-hydroxy-2-(phosphonomethoxy)propyl]purines/pyrimidines (adenine, HPMPA; guanine, HPMPG; cytosine, HPMPC) are devoid of antiherpesvirus activity. This result confirms that the beta-oxygen atom of the phosphonomethyl ether functionality in HPMP-purines/pyrimidines plays a critical role for activity against herpesviruses.
发现阿昔洛韦（ACV）和更昔洛韦（DHPG）单磷酸盐的新型膦酸酯类似物是强效且选择性的抗疱疹病毒药物。在ACV单磷酸盐的膦酸酯类似物系列中，只有鸟嘌呤类似物20对疱疹病毒具有活性，这与ACV类似物碱基修饰所观察到的构效关系相似。ACV单磷酸盐的膦酸酯类似物（20）在单纯疱疹病毒1型（HSV-1）感染的小鼠模型中比ACV更有效。9-[3-羟基-2-(膦酰甲氧基)丙基]嘌呤/嘧啶（腺嘌呤，HPMPA；鸟嘌呤，HPMPG；胞嘧啶，HPMPC）的3'-碳环类似物没有抗疱疹病毒活性。这一结果证实，HPMP-嘌呤/嘧啶中膦酰甲醚官能团的β-氧原子对其抗疱疹病毒活性起着关键作用。
