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Narlaprevir is a potent and second generation inhibitor of HCV NS3 protease with Ki value of 6 nM [1].

HCV infection is a global problem of public health. It can even cause liver cirrhosis and hepatocellular carcinoma. As an essential enzyme of HCV replication, NS3 serine protease is thought to be an attractive target for HCV infection treatment. Narlaprevir is one of the small inhibitors of NS3 protease. Unlike boceprevir, narlaprevir is a single isoform and shows improved potency. In the inhibiting process of NS3 protease, narlaprevir firstly binds the enzyme with noncovalent interactions and then binds the active-site Ser139 with a reversible covalent bond [1, 2 and 3].

In the in vitro assay, narlaprevir inhibited genotyoes 1a, 1b, 2a and 3a NS3 proteases with Ki values of 0.7, 7, 3 and 7 nM, respectively. In the virus replicon-inhibition assay, narlaprevir showed significant antiviral efficacy with EC50 and EC90 values of 20 and 40 nM, respectively. Besides that, narlaprevir had no cytotoxicity for the host cells. Narlaprevir is also used as a combination therapy with pegylated interferon. The combination treatment of narlaprevir and interferon alfa-2b showed elevated activity in replicon inhibition than the monotherapy of narlaprevir alone [2].

Narlaprevir has improved pharmacokinetic profile of both AUC and bioavailability in animal trials. It showed AUC of 6.5 μM·h, 1.1 μM·h and 0.9 μM·h in rats, monkeys and dogs, respectively. The bioavailabilities of narlaprevir in the three kinds of animals are 46%, 46% and 29%, respectively [1].

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