Schering Plough Research Institute, K15-MS 3545, 2015, Galloping Hill Road, Kenilworth, NJ 07033, United States.
Bioorg Med Chem Lett. 2010 Apr 1;20(7):2151-5. doi: 10.1016/j.bmcl.2010.02.051. Epub 2010 Feb 14.
Blood borne hepatitis C infections are the primary cause for liver cirrhosis and hepatocellular carcinoma. HCV NS3 protease, a pivotal enzyme in the replication cycle of HCV virus has been the primary target for development of new drug candidates. Boceprevir and telaprevir are two novel ketoamide derived inhibitors that are currently undergoing phase-III clinical trials. These inhibitors include ketoamide functionality as serine trap and have an acidic alpha-ketoamide center that undergoes epimerization under physiological conditions. Our initial attempts to arrest this epimerization by introducing quaternary amino acids at P(1) had resulted in significantly diminished activity. In this manuscript we describe alpha quaternized P(1) group that result in potent inhibitors in the enzyme assay and demonstrate cellular activity comparable to boceprevir.
血源性丙型肝炎感染是肝硬化和肝细胞癌的主要原因。丙型肝炎病毒 NS3 蛋白酶是丙型肝炎病毒复制周期中的关键酶,一直是开发新药候选物的主要目标。波西普韦和特拉普韦是两种新型酮酰胺衍生抑制剂,目前正在进行 III 期临床试验。这些抑制剂包括酮酰胺功能作为丝氨酸陷阱,并具有酸性α-酮酰胺中心,在生理条件下经历差向异构化。我们最初试图通过在 P(1)处引入季铵氨基酸来阻止这种差向异构化,结果导致活性显著降低。在本文中,我们描述了α季铵化的 P(1)基团,它们在酶测定中产生有效的抑制剂,并证明具有与波西普韦相当的细胞活性。