Innaimo S F, Seifer M, Bisacchi G S, Standring D N, Zahler R, Colonno R J
Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492-7660, USA.
Antimicrob Agents Chemother. 1997 Jul;41(7):1444-8. doi: 10.1128/AAC.41.7.1444.
BMS-200475 is a novel carbocyclic 2'-deoxyguanosine analog found to possess potent and selective anti-hepatitis B virus (anti-HBV) activity. BMS-200475 is distinguished from guanosine by replacement of the natural furanose oxygen on the sugar moiety with an exo carbon-carbon double bond. In the HepG2 stably transfected cell line 2.2.15, BMS-200475 had a 50% effective concentration (EC50) of 3.75 nM against HBV, as determined by analysis of secreted HBV DNA. Structurally related compounds with adenine, iodouracil, or thymine base substitutions were significantly less potent or were inactive. Direct comparison of the antiviral activities of BMS-200475 with those of a variety of other nucleoside analogs, including lamivudine (EC50 = 116.26 nM), demonstrated the clearly superior in vitro potency of BMS-200475 in 2.2.15 cells. Intracellular HBV replicative intermediates were uniformly reduced when cells were treated with BMS-200475, but rebounded after treatment was terminated. The concentration of BMS-200475 causing 50% cytotoxicity in 2.2.15 cell cultures was 30 microM, approximately 8,000-fold greater than the concentration required to inhibit HBV replication in the same cell line. Treatment with BMS-200475 resulted in no apparent inhibitory effects on mitochondrial DNA content.
BMS-200475是一种新型碳环2'-脱氧鸟苷类似物，具有强效且选择性的抗乙型肝炎病毒（抗HBV）活性。BMS-200475与鸟苷的区别在于，其糖部分的天然呋喃糖氧被一个外环碳-碳双键取代。在稳定转染的HepG2细胞系2.2.15中，通过分析分泌的HBV DNA，BMS-200475对HBV的50%有效浓度（EC50）为3.75 nM。具有腺嘌呤、碘尿嘧啶或胸腺嘧啶碱基取代的结构相关化合物的效力显著较低或无活性。将BMS-200475的抗病毒活性与包括拉米夫定（EC50 = 116.26 nM）在内的多种其他核苷类似物的抗病毒活性进行直接比较，结果表明BMS-200475在2.2.15细胞中的体外效力明显更强。用BMS-200475处理细胞时，细胞内HBV复制中间体均减少，但在处理终止后又反弹。在2.2.15细胞培养物中引起50%细胞毒性的BMS-200475浓度为30 μM，约为抑制同一细胞系中HBV复制所需浓度的8000倍。用BMS-200475处理对线粒体DNA含量没有明显的抑制作用。
