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首页> 外文期刊>Antimicrobial agents and chemotherapy. >MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants
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MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants

机译：MK-5172，丙型肝炎病毒NS3 / 4a蛋白酶的选择性抑制剂，在基因型和耐药变异中具有广泛的活性

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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.
机译：HCV NS3 / 4a蛋白酶抑制剂已被证明是抗慢性丙型肝炎病毒感染的治疗剂，boceprevir和telaprevir最近已获得监管批准，作为聚乙二醇化干扰素/利巴韦林的附加疗法，用于携带基因型1感染的患者。克服抗病毒耐药性，广泛的基因型覆盖范围和方便的给药方案是将来在无干扰素的情况下联合使用的重要指标。在此通讯中，我们报告了目前正在临床开发中的新型P2-P4喹喔啉大环NS3 / 4a蛋白酶抑制剂MK-5172的临床前概况。该化合物对包括主要丙型肝炎病毒（HCV）基因型以及对早期蛋白酶抑制剂具有抗性的变体在内的广泛酶组成部分表现出亚纳摩尔活性。在复制子选择中，MK-5172施加高选择压力，产生的抗性菌落很少。在大鼠和狗中，MK-5172均表现出良好的血浆和肝脏暴露，且24小时肝脏水平提示每天一次给药。当对具有慢性gt1a或gt1b慢性感染的HCV感染的黑猩猩给药时，MK-5172每天两次（b.i.d.）以1 mg / kg体重的剂量将病毒载量抑制在4至5个对数之间，持续7天。基于其临床前概况，MK-5172有望对多种HCV基因型和临床上重要的耐药变异体具有广泛的活性，并且非常适合纳入新的全口服方案中。

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