Inhibitors of the hepatitis C virus RNA-dependent RNA polymerase

被引：11

作者：

Colarusso, Stefania ^{[1
]}

Attenni, Barbara ^{[1
]}

Avolio, Salvatore ^{[1
]}

Malancona, Savina ^{[1
]}

Harper, Steven ^{[1
]}

Altamura, Sergio ^{[1
]}

Koch, Uwe ^{[1
]}

Narjes, Frank ^{[1
]}

机构：

[1] P Angeletti SpA, Merck Res Labs, Ist Ric Biol Mol, Via Pontina Km 30,000, I-00040 Pomezia, Italy

来源：

ARKIVOC | 2006年

关键词：

hepatitis C virus; NS5B polymerase; pyrimidines; N1-substituted pyrimidones; pyridine-N-oxides;

D O I：

10.3998/ark.5550190.0007.733

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

Infections caused by Hepatitis C Virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed diketoacids 1 and dihydroxypyrimidine carboxylates 3 as novel, reversible inhibitors of the HCV NS5B polymerase. We report here the further development of 3 into the more potent 5,6-dihydroxy-2-(2-thienyl) pyrimidine-4-carboxylic acids. The structure activity relationship of these inhibitors is discussed in the context of their physicochemical properties, supporting the proposed binding model, which involves pyrophosphate like chelation of the active site Mg-ions. We also report on the discovery and synthesis of two related scaffolds, the N1-substituted pyrimidones and pyridine-N-oxides.

引用

页码：479 / 495

页数：17

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