Background:

Asunaprevir is an orally efficacious inhibitor of NS3 protease with IC50 value of 1nM [1].

Asunaprevir is an inhibitor of hepatitis C virus (HCV) NS3 protease. It can inhibit 6 major genotypes of HCV NS3/4A protease with IC50 values of 0.7nM, 0.3nM, 15nM, 78nM, 320nM, 1.6nM, 1.7nM and 0.9nM, respectively for genotype 1a, 1b, 2a, 2b, 3a, 4a, 5a and 6a, respectively. When using the purified recombinant full-length HCV NS3/4A protease complexes, asunaprevir shows the Ki values of 0.4nM and 0.2nM, respectively for genotype 1a and genotype 1b. The mechanism of the inhibition is that the acylsulfonamide of asunaprevir interacts with the catalytic site of NS3 protease in a noncovalent manner. Asunaprevir inhibits HCV RNA replication in different cell lines, including liver, T lymphocytes, lung, cervix, and embryonic kidney. It shows no obvious activity against other RNA viruses. The permeability of asunaprevir is similar to the compound with good absorption in humans. The tests of metabolism rate show that asunaprevir exhibits low to intermediate metabolic clearance. Plasma and tissue exposures in vivo indicate that asunaprevir displays a hepatotropic disposition [2].

参考文献:
[1] Scola PM, Sun LQ, Wang AX, Chen J, Sin N, Venables BL, Sit SY, Chen Y, Cocuzza A, Bilder DM, D'Andrea SV, Zheng B, Hewawasam P, Tu Y, Friborg J, Falk P, Hernandez D, Levine S, Chen C, Yu F, Sheaffer AK, Zhai G, Barry D, Knipe JO, Han YH, Schartman R, Donoso M, Mosure K, Sinz MW, Zvyaga T, Good AC, Rajamani R, Kish K, Tredup J, Klei HE, Gao Q, Mueller L, Colonno RJ, Grasela DM, Adams SP, Loy J, Levesque PC, Sun H, Shi H, Sun L, Warner W, Li D, Zhu J, Meanwell NA, McPhee F. The discovery of asunaprevir (BMS-650032), an orally efficacious NS3 protease inhibitor for the treatment of hepatitis C virus infection. J Med Chem. 2014 Mar 13;57(5):1730-52.
[2] McPhee F, Sheaffer AK, Friborg J, Hernandez D, Falk P, Zhai G, Levine S, Chaniewski S, Yu F, Barry D, Chen C, Lee MS, Mosure K, Sun LQ, Sinz M, Meanwell NA, Colonno RJ, Knipe J, Scola P. Preclinical Profile and Characterization of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir (BMS-650032). Antimicrob Agents Chemother. 2012 Oct;56(10):5387-96.