Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors

被引：61

作者：

Li, Hui

Tatlock, John

Linton, Angelica

Gonzalez, Javier

Borchardt, Allen

Dragovich, Peter

Jewell, Tanya

Prins, Tom

Zhou, Ru

Blazel, Julie

Parge, Hans

Love, Robert

Hickey, Michael

Doan, Chau

Shi, Stephanie

Duggal, Rohit

Lewis, Cristina

Fuhrman, Shella

机构：

[1] La Jolla Labs, Pfizer Global Res & Dev, San Diego, CA 92121 USA

[2] Anadys Pharmaceut, San Diego, CA 92121 USA

[3] Genentech Inc, San Francisco, CA 94098 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 18期

关键词：

HCV polymerase; dihydropyrone; structure-based drug design;

D O I：

10.1016/j.bmcl.2006.06.065

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel class of non-nucleoside HCV NS5B polymerase inhibitors has been identified from screening. A co-crystal structure revealed an allosteric binding site in the protein that required a unique conformational change to accommodate inhibitor binding. Herein we report the structure-activity relationships (SARs) of this novel class of dihydropyrone-containing compounds that show potent inhibitory activities against the HCV RNA polymerase in biochemical assays. (c) 2006 Elsevier Ltd. All rights reserved.

引用

页码：4834 / 4838

页数：5

共 16 条

[1]

Beaulieu Pierre L, 2004, Curr Opin Investig Drugs, V5, P838

[2] Identification and properties of the RNA-dependent RNA polymerase of hepatitis C virus [J].

Behrens, SE ;

Tomei, L ;

DeFrancesco, R .

EMBO JOURNAL, 1996, 15 (01) :12-22

[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] Identification and biological characterization of heterocyclic inhibitors of the hepatitis C virus RNA-dependent RNA polymerase [J].

Dhanak, D ;

Duffy, KJ ;

Johnston, VK ;

Lin-Goerke, J ;

Darey, M ;

Shaw, AN ;

Gu, BH ;

Silverman, C ;

Gates, AT ;

Nonnemacher, MR ;

Earnshaw, DL ;

Casper, DJ ;

Kaura, A ;

Baker, A ;

Greenwood, C ;

Gutshall, LL ;

Maley, D ;

DelVecchio, A ;

Macarron, R ;

Hofmann, GA ;

Alnoah, Z ;

Cheng, HY ;

Chan, G ;

Khandekar, S ;

Keenan, RM ;

Sarisky, RT .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (41) :38322-38327

[7] Interdomain communication in hepatitis C virus polymerase abolished by small molecule inhibitors bound to a novel allosteric site [J].

Di Marco, S ;

Volpari, C ;

Tomei, L ;

Altamura, S ;

Harper, S ;

Narjes, F ;

Koch, U ;

Rowley, M ;

De Francesco, R ;

Migliaccio, G ;

Carfí, A .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (33) :29765-29770

[8] Antiviral therapy for chronic hepatitis C: past, present, and future [J].

Hayashi, N ;

Takehara, T .

JOURNAL OF GASTROENTEROLOGY, 2006, 41 (01) :17-27

[9] Binding site characterization and resistance to a class of non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase [J].

Kukolj, G ;

McGibbon, GA ;

McKercher, G ;

Marquis, M ;

Lefèbvre, S ;

Thauvette, L ;

Gauthier, J ;

Goulet, S ;

Poupart, MA ;

Beaulieu, PL .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (47) :39260-39267

[10] Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line [J].

Lohmann, V ;

Körner, F ;

Koch, JO ;

Herian, U ;

Theilmann, L ;

Bartenschlager, R .

SCIENCE, 1999, 285 (5424) :110-113

← 1 2 →