HCVNS5b RNA-dependent RNA polymerase inhibitors:: From α,γ-diketoacids to 4,5-dihydroxypyrimidine- or 3-methyl-5-hydroxypyrimidinonecarboxylic acids.: Design and synthesis

被引：94

作者：

Summa, V

Petrocchi, A

Matassa, VG

Taliani, M

Laufer, R

De Francesco, R

Altamura, S

Pace, P

机构：

[1] IRBM, Dept Med Chem, MRL Rome, I-00040 Pomezia, RM, Italy

[2] IRBM, Dept Biochem, MRL Rome, I-00040 Pomezia, RM, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2004年 / 47卷 / 22期

关键词：

D O I：

10.1021/jm0494669

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new class of the HCV NS5b RNA-dependent RNA polymerase inhibitors, the dihyroxypyrimidinecarboxylic acid derivative, was designed from a diketoacid and meconic acid derivative discovered by screening. Mechanism of action and essential moieties required for activity were identified. The corresponding N-methylpyrimidinone was also prepared; both classes are novel, reversible, and selective inhibitors of the HCV NS5b polymerase with improved druglike characteristics.

引用

页码：5336 / 5339

页数：4

共 22 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] Inhibition of hepatitis C virus RNA replication by 2′-modified nucleoside analogs [J].

Carroll, SS ;

Tomassini, JE ;

Bosserman, M ;

Getty, K ;

Stahlhut, MW ;

Eldrup, AB ;

Bhat, B ;

Hall, D ;

Simcoe, AL ;

LaFemina, R ;

Rutkowski, CA ;

Wolanski, B ;

Yang, ZC ;

Migliaccio, G ;

De Francesco, R ;

Kuo, LC ;

MacCoss, M ;

Olsen, DB .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (14) :11979-11984

[4] 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

[5] 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

[6] 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

[7] ISOLATION OF A CDNA CLONE DERIVED FROM A BLOOD-BORNE NON-A, NON-B VIRAL-HEPATITIS GENOME [J].

CHOO, QL ;

KUO, G ;

WEINER, AJ ;

OVERBY, LR ;

BRADLEY, DW ;

HOUGHTON, M .

SCIENCE, 1989, 244 (4902) :359-362

[8]

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

[9] 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

[10] SYNTHESIS OF 5,6-DIHYDROXY-2-PHENYL-4-PYRIMIDINECARBOXYLIC ACID, METHYL-ESTER, A CORRECTED STRUCTURE [J].

CULBERTSON, TP .

JOURNAL OF HETEROCYCLIC CHEMISTRY, 1979, 16 (07) :1423-1424

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