Phosphoramidate Prodrugs of 2′-C-Methylcytidine for Therapy of Hepatitis C Virus Infection

被引：47

作者：

Gardelli, Cristina ^{[1
,2
]}

Attenni, Barbara ^{[1
,2
]}

Donghi, Monica ^{[1
,2
]}

Meppen, Malte ^{[1
,2
]}

Pacini, Barbara ^{[1
,2
]}

Harper, Steven ^{[1
,2
]}

Di Marco, Annalise ^{[1
,2
]}

Fiore, Fabrizio ^{[1
,2
]}

Giuliano, Claudio ^{[1
,2
]}

Pucci, Vincenzo ^{[1
,2
]}

Laufer, Ralph ^{[1
,2
]}

Gennari, Nadia ^{[1
,2
]}

Marcucci, Isabella ^{[1
,2
]}

Leone, Joseph F. ^{[3
]}

Olsen, David B. ^{[4
]}

MacCoss, Malcolm ^{[3
]}

Rowley, Michael ^{[1
,2
]}

Narjes, Frank ^{[1
,2
]}

机构：

[1] Ist Ric Biol Mol P Angeletti SpA, IRBM, MRL Rome, Dept Med Chem, I-00040 Pomezia, Italy

[2] Ist Ric Biol Mol P Angeletti SpA, IRBM, MRL Rome, Dept Pharmacol, I-00040 Pomezia, Italy

[3] Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA

[4] Merck Res Labs, Dept Antiviral Res, West Point, PA 19486 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 17期

关键词：

HCV AGENT 2'-C-METHYLCYTIDINE; DEPENDENT RNA-POLYMERASE; ANTIVIRAL POTENCY; NS5B POLYMERASE; 2,3-DIDEHYDRO-2,3-DIDEOXYADENOSINE D4A; PROTEASE INHIBITORS; EFFICIENT PRODRUG; RECENT PROGRESS; NUCLEOSIDE; DERIVATIVES;

D O I：

10.1021/jm900447q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The application of a phosphoramidate prodrug approach to 2'-C-methylcytidine (NM107), the first nucleoside inhibitor of the hepatitis C virus (HCV) NS5B polymerase, is reported. 2'-C-Methylcytidine, as its valyl ester prodrug (NM283), was efficacious in reducing the viral load in patients infected with HCV. Several of the phosphoramidates prepared demonstrated a 10- to 200-fold superior potency with respect to the parent nucleoside in the cell-based replicon assay. This is due to higher levels of 2'-C-methylcytidine triphosphate in the cells. These prodrugs are efficiently activated and converted to the triphosphate in hepatocytes of several species. Our SAR studies ultimately led to compounds that gave high levels of NTP in hamster and rat liver after subcutaneous dosing and that were devoid of the toxic phenol moiety usually found in ProTides.

引用

页码：5394 / 5407

页数：14

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