Istituto Di Ricerche Di Biologia Molecolare, P. Angeletti SpA (Merck Research Laboratories, Rome), Pomezia, Italy.
J Med Chem. 2011 Jan 13;54(1):289-301. doi: 10.1021/jm1013105. Epub 2010 Dec 8.
Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain. Structure-activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate. The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.
丙型肝炎病毒（HCV）感染是一个严重的全球健康问题，因此急需新型疗法。HCV 的聚合酶负责病毒基因组的复制，一直是药物发现努力的主要目标。在这里，我们报告了四环吲哚抑制剂的进一步开发，该抑制剂结合在拇指结构域的变构位点上。围绕吲哚并苯并恶嗪骨架的结构-活性关系（SAR）研究导致了化合物 33（MK-3281）的鉴定，该化合物在 HCV 亚基因组复制测定中具有良好的效力，并且具有适合临床候选药物的有吸引力的分子特性。该化合物在使用 HCV 感染嵌合小鼠模型的体内实验中导致病毒血症持续下降。
