MK-5172, a Selective Inhibitor of Hepatitis C Virus NS3/4a Protease with Broad Activity across Genotypes and Resistant Variants
MK-5172, a Selective Inhibitor of Hepatitis C Virus NS3/4a Protease with Broad Activity across Genotypes and Resistant Variants
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DOI：
10.1128/aac.00324-12
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发表时间：
2012-08-01
影响因子：
4.9
通讯作者：
Carroll, Steven S.
中科院分区：
文献类型：
--
作者：
Summa, Vincenzo;Ludmerer, Steven W.;Carroll, Steven S.
丙型肝炎病毒（HCV）NS3/4a蛋白酶抑制剂是已被证实的治疗慢性丙型肝炎病毒感染的药物，博赛泼维和特拉匹韦最近已获监管部门批准，作为聚乙二醇干扰素/利巴韦林的附加疗法，用于基因1型感染患者。克服抗病毒耐药性、广泛的基因型覆盖以及便捷的给药方案是未来用于无干扰素联合治疗药物的重要特性。在本文中，我们报道了MK - 5172的临床前特征，它是一种新型的P2 - P4喹喔啉大环NS3/4a蛋白酶抑制剂，目前正处于临床开发阶段。该化合物对涵盖主要丙型肝炎病毒（HCV）基因型以及对早期蛋白酶抑制剂耐药的变体的广泛酶组表现出亚纳摩尔级活性。在复制子筛选中，MK - 5172施加了高选择压力，产生的耐药菌落很少。在大鼠和犬中，MK - 5172显示出良好的血浆和肝脏暴露量，24小时肝脏水平提示可每日给药一次。当给予患有慢性基因1a型或基因1b型感染的丙型肝炎病毒感染黑猩猩时，MK - 5172在每日两次（b.i.d.）、剂量为1mg/kg体重的情况下给药7天，可将病毒载量抑制4 - 5个对数级。基于其临床前特征，预计MK - 5172对多种丙型肝炎病毒基因型和具有临床重要性的耐药变体具有广泛活性，非常适合纳入更新的全口服治疗方案。
HCV NS3/4a protease inhibitors are proven therapeutic agents against chronic hepatitis C virus infection, with boceprevir and telaprevir having recently received regulatory approval as add-on therapy to pegylated interferon/ribavirin for patients harboring genotype 1 infections. Overcoming antiviral resistance, broad genotype coverage, and a convenient dosing regimen are important attributes for future agents to be used in combinations without interferon. In this communication, we report the preclinical profile of MK-5172, a novel P2-P4 quinoxaline macrocyclic NS3/4a protease inhibitor currently in clinical development. The compound demonstrates subnanomolar activity against a broad enzyme panel encompassing major hepatitis C virus (HCV) genotypes as well as variants resistant to earlier protease inhibitors. In replicon selections, MK-5172 exerted high selective pressure, which yielded few resistant colonies. In both rat and dog, MK-5172 demonstrates good plasma and liver exposures, with 24-h liver levels suggestive of once-daily dosing. When administered to HCV-infected chimpanzees harboring chronic gt1a or gt1b infections, MK-5172 suppressed viral load between 4 to 5 logs at a dose of 1 mg/kg of body weight twice daily (b.i.d.) for 7 days. Based on its preclinical profile, MK-5172 is anticipated to be broadly active against multiple HCV genotypes and clinically important resistance variants and highly suited for incorporation into newer all-oral regimens.