Discovery of SCH446211 (SCH6): A new ketoamide inhibitor of the HCV NS3 serine protease and HCV subgenomic RNA replication

被引：45

作者：

Bogen, SL

Arasappan, A

Bennett, F

Chen, K

Jao, E

Liu, YT

Lovey, RG

Venkatraman, S

Pan, WD

Parekh, T

Pike, RE

Ruan, S

Liu, R

Baroudy, B

Agrawal, S

Chase, R

Ingravallo, P

Pichardo, J

Prongay, A

Brisson, JM

Hsieh, TY

Cheng, KC

Kemp, SJ

Levy, OE

Lim-Wilby, M

Tamura, SY

Saksena, AK

Girijavallabhan, V

Njoroge, FG

机构：

[1] Schering Plough Res Inst, Kenilworth, NJ 07033 USA

[2] Dendreon Corp, Seattle, WA 98121 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 09期

关键词：

D O I：

10.1021/jm060077j

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Introduction of various modified prolines at P-2 and optimization of the P-1 side chain led to the discovery of SCH6 (24, Table 2), a potent ketoamide inhibitor of the HCV NS3 serine protease. In addition to excellent enzyme potency (K-i* = 3.8 nM), 24 was also found to be a potent inhibitor of HCV subgenomic RNA replication with IC50 and IC90 of 40 and 100 nM, respectively. Recently, antiviral activity of 24 was demonstrated with inhibition of the full-length genotype 2a HCV genome. In addition, 24 was found to restore the responsiveness of the interferon regulatory factor 3 (IRF-3) in cells containing HCV RNA replicons.

引用

页码：2750 / 2757

页数：8

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