The introduction of P4 substituted 1-methylcyclohexyl groups into Boceprevir®: A change in direction in the search for a second generation HCV NS3 protease inhibitor

被引：27

作者：

Bennett, Frank ^{[1
]}

Huang, Yuhua ^{[1
]}

Hendrata, Siska ^{[1
]}

Lovey, Raymond ^{[1
]}

Bogen, Stephane L. ^{[1
]}

Pan, Weidong ^{[1
]}

Guo, Zhuyan ^{[1
]}

Prongay, Andrew ^{[1
]}

Chen, Kevin X. ^{[1
]}

Arasappan, Ashok ^{[1
]}

Venkatraman, Srikanth ^{[1
]}

Velazquez, Francisco ^{[1
]}

Nair, Latha ^{[1
]}

Sannigrahi, Mousumi ^{[1
]}

Tong, Xiao ^{[1
]}

Pichardo, John ^{[1
]}

Cheng, Kuo-Chi ^{[1
]}

Girijavallabhan, Viyyoor M. ^{[1
]}

Saksena, Anil K. ^{[1
]}

Njoroge, F. George ^{[1
]}

机构：

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 08期

关键词：

HEPATITIS-C VIRUS; PEGINTERFERON ALPHA-2B; OPTIMIZATION; DISCOVERY; POTENT; REPLICATION; CHALLENGES; STRATEGIES; RIBAVIRIN;

D O I：

10.1016/j.bmcl.2010.02.063

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In the search for a second generation HCV protease inhibitor, molecular modeling studies of the X-ray crystal structure of Boceprevir (R) 1 bound to the NS3 protein suggest that expansion into the S4 pocket could provide additional hydrophobic Van der Waals interactions. Effective replacement of the P4 tertbutyl with a cyclohexylmethyl ligand led to inhibitor 2 with improved enzyme and replicon activities. Subsequent modeling and SAR studies led to the pyridine 38 and sulfone analogues 52 and 53 with vastly improved PK parameters in monkeys, forming a new foundation for further exploration. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：2617 / 2621

页数：5

共 30 条

[1] Pyrrolidine-5,5-trans-lactams.: 5.: Pharmacokinetic optimization of inhibitors of hepatitis C virus NS3/4A protease [J].