Parallel synthesis of pteridine derivatives as potent inhibitors for hepatitis C virus NS5B RNA-dependent RNA polymerase

被引：38

作者：

Ding, Y ^{[1
]}

Girardet, JL ^{[1
]}

Smith, KL ^{[1
]}

Larson, G ^{[1
]}

Prigaro, B ^{[1
]}

Lai, VCH ^{[1
]}

Zhong, WD ^{[1
]}

Wu, JZ ^{[1
]}

机构：

[1] Valeant Pharmaceut Int, Costa Mesa, CA 92626 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2005年 / 15卷 / 03期

关键词：

HCV; inhibitor; NS5B; pteridine;

D O I：

10.1016/j.bmcl.2004.11.028

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

From compound library screening using an HCV NS5B RNA-dependent RNA polymerase enzymatic assay, we identified a pteridine hit compound with an IC50 of 15 muM. Our SAR studies were focused on the different groups at the 6- and 7-positions. substitutions at the 4-position, and replacement of N-1 or N-3 with carbon in the pteridine ring. We found that NH or OH at 4-position is critical for the inhibitory activity. Furthermore, a hydrophobic substituent at the 4-position may help compounds permeate through the cell membrane. (C) 2004 Elsevier Ltd. All rights reserved.

引用

页码：675 / 678

页数：4

共 23 条

[1] Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase:: discovery of benzimidazole 5-carboxylic amide derivatives with low-nanomolar potency [J].

Beaulieu, PL ;

Bös, M ;

Bousquet, Y ;

DeRoy, P ;

Fazal, G ;

Gauthier, J ;

Gillard, J ;

Goulet, S ;

McKercher, G ;

Poupart, MA ;

Valois, S ;

Kukolj, G .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (04) :967-971

[2] Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase:: discovery and preliminary SAR of benzimidazole derivatives [J].

Beaulieu, PL ;

Bös, M ;

Bousquet, Y ;

Fazal, G ;

Gauthier, J ;

Gillard, J ;

Goulet, S ;

LaPlante, S ;

Poupart, MA ;

Lefebvre, S ;

McKercher, G ;

Pellerin, C ;

Austel, V ;

Kukolj, G .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (01) :119-124

[3] Discovery of thiophene-2-carboxylic acids as potent inhibitors of HCVNS5B polymerase and HCV subgenomic RNA replication.: Part 1:: Sulfonamides [J].

Chan, L ;

Das, SK ;

Reddy, TJ ;

Poisson, C ;

Proulx, M ;

Pereira, O ;

Courchesne, M ;

Roy, C ;

Wang, WY ;

Siddiqui, A ;

Yannopoulos, CG ;

Nguyen-Ba, N ;

Labrecque, D ;

Bethell, R ;

Hamel, M ;

Courtemanche-Asselin, P ;

L'Heureux, L ;

David, M ;

Nicolas, O ;

Brunette, S ;

Bilimoria, D ;

Bédard, J .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (03) :793-796

[4] Discovery of thiophene-2-carboxylic acids as potent inhibitors of HCVNS5B polymerase and HCV subgenomic RNA replication.: Part 2:: Tertiary amides [J].

Chan, L ;

Pereira, O ;

Reddy, TJ ;

Das, SK ;

Poisson, C ;

Courchesne, M ;

Proulx, M ;

Siddiqui, A ;

Yannopoulos, CG ;

Nguyen-Ba, N ;

Roy, C ;

Nasturica, D ;

Moinet, C ;

Bethell, R ;

Hamel, M ;

L'Heureux, L ;

David, M ;

Nicolas, O ;

Courtemanche-Asselin, P ;

Brunette, S ;

Bilimoria, D ;

Bédard, J .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (03) :797-800

[5] Identification of N,N-disubstituted phenylalanines as a novel class of inhibitors of hepatitis CNS5B polymerase [J].

Chan, L ;

Reddy, TJ ;

Proulx, M ;

Das, SK ;

Pereira, O ;

Wang, WY ;

Siddiqui, A ;

Yannopoulos, CG ;

Poisson, C ;

Turcotte, N ;

Drouin, A ;

Alaoui-Ismaili, MH ;

Bethell, R ;

Hamel, M ;

L'Heureux, L ;

Bilimoria, D ;

Nguyen-Ba, N .

JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (08) :1283-1285

[6] Treatment of chronic hepatitis C: A systematic review [J].

Chander, G ;

Sulkowski, MS ;

Jenckes, MW ;

Torbenson, MS ;

Herlong, HF ;

Bass, EB ;

Gebo, KA .

HEPATOLOGY, 2002, 36 (05) :S135-S144

[7]

Cornberg M, 2003, Z GASTROENTEROL, V41, P517, DOI 10.1055/s-2003-39649

[8] Treatment of chronic hepatitis C with PEGylated interferon and ribavirin. [J].

Cornberg M. ;

Wedemeyer H. ;

Manns M.P. .

Current Gastroenterology Reports, 2002, 4 (1) :23-30

[9] Optimal therapy of hepatitis C [J].

Di Bisceglie, AM ;

Hoofnagle, JH .

HEPATOLOGY, 2002, 36 (05) :S121-S127

[10]

Dymock B W, 2001, Expert Opin Emerg Drugs, V6, P13, DOI 10.1517/14728214.6.1.13

← 1 2 3 →