Evaluation of 2′-α-fluorine modified nucleoside phosphonates as potential inhibitors of HCV polymerase

被引：10

作者：

Parrish, Jay P. ^{[1
]}

Lee, Sharon K. ^{[1
]}

Boojamra, Constantine G. ^{[1
]}

Hui, Hon ^{[1
]}

Babusis, Darius ^{[1
]}

Brown, Brandon ^{[1
]}

Shih, I-hung ^{[1
]}

Feng, Joy Y. ^{[1
]}

Ray, Adrian S. ^{[1
]}

Mackman, Richard L. ^{[1
]}

机构：

[1] Gilead Sci Inc, Foster City, CA 94404 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 11期

关键词：

Hepatitis C; HCV; Nucleosides; NS5b; Polymerase; HCV NS5b polymerase; C VIRUS-REPLICATION; ANTI-HIV ACTIVITY; ANTIVIRAL ACTIVITY; RNA-SYNTHESIS; ANALOGS; DESIGN; MECHANISM; PRODRUG; BETA-D-2'-DEOXY-2'-FLUORO-2'-C-METHYLCYTIDINE; RIBONUCLEOSIDES;

D O I：

10.1016/j.bmcl.2013.03.095

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Ribonucleoside phosphonate analogues containing 2'-alpha-fluoro modifications were synthesized and their potency evaluated against HCV RNA polymerase. The diphosphophosphonate (triphosphate equivalent) adenine and cytidine analogues displayed potent inhibition of the HCV polymerase in the range of 1.9-2.1 mu M, but only modest cell-based activity in the HCV replicon. Pro- drugs of the parent nucleoside phosphonates improved the cell-based activity. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：3354 / 3357

页数：4

共 38 条

[1]

[Anonymous], 2008, [No title captured], Patent No. [WO 2008/005542, 2008005542]

[2] Cathepsin A is the major hydrolase catalyzing the intracellular hydrolysis of the antiretroviral nucleotide phosphonoamidate prodrugs GS-7340 and GS-9131 [J].

Birkus, Gabriel ;

Wang, Ruth ;

Liu, Xiaohong ;

Kutty, Nilima ;

MacArthur, Holly ;

Cihlar, Tomas ;

Gibbs, Craig ;

Swaminathan, Swami ;

Lee, William ;

McDermott, Martin .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2007, 51 (02) :543-550

[3] Synthesis and anti-HIV activity novel nucleoside phosphonate HIV of GS-9148 (2′-Fd4AP), a reverse transcriptase inhibitor [J].

Boojamra, Constantine G. ;

Mackman, Richard L. ;

Markevitch, David Y. ;

Prasad, Vidya ;

Ray, Adrian S. ;

Douglas, Janet ;

Grant, Deborah ;

Kim, Choung U. ;

Cihlar, Tomas .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (03) :1120-1123

[4] Discovery of PSI-353661, a Novel Purine Nucleotide Prodrug for the Treatment of HCV Infection [J].

Chang, Wonsuk ;

Bao, Donghui ;

Chun, Byoung-Kwon ;

Naduthambi, Devan ;

Nagarathnam, Dhanapalan ;

Rachakonda, Suguna ;

Reddy, P. Ganapati ;

Ross, Bruce S. ;

Zhang, Hai-Ren ;

Bansal, Shalini ;

Espiritu, Christine L. ;

Keilman, Meg ;

Lam, Angela M. ;

Niu, Congrong ;

Steuer, Holly Micolochick ;

Furman, Phillip A. ;

Otto, Michael J. ;

Sofia, Michael J. .

ACS MEDICINAL CHEMISTRY LETTERS, 2011, 2 (02) :130-135

[5]

CHEN JM, 2008, Patent No. 2008100447

[6]

Chen Stephen L, 2006, Int J Med Sci, V3, P47

[7] Design and profiling of GS-9148, a novel nucleotide analog active against nucleoside-resistant variants of human immunodeficiency virus type 1, and its orally bioavailable phosphonoamidate prodrug, GS-9131 [J].

Cihlar, Tomas ;

Ray, Adrian S. ;

Boojamra, Constantine G. ;

Zhang, Lijun ;

Hui, Hon ;

Laflamme, Genevieve ;

Vela, Jennifer E. ;

Grant, Deborah ;

Chen, James ;

Myrick, Florence ;

White, Kirsten L. ;

Gao, Ying ;

Lin, Kuei-Ying ;

Douglas, Janet L. ;

Parkin, Neil T. ;

Carey, Anne ;

Pakdaman, Rowchanak ;

Mackman, Richard L. .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2008, 52 (02) :655-665

[8] Novel Nucleotide Human Immunodeficiency Virus Reverse Transcriptase Inhibitor GS-9148 with a Low Nephrotoxic Potential: Characterization of Renal Transport and Accumulation [J].

Cihlar, Tomas ;

LaFlamme, Genevieve ;

Fisher, Robyn ;

Carey, Anne C. ;

Vela, Jennifer E. ;

Mackman, Richard ;

Ray, Adrian S. .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2009, 53 (01) :150-156

[9] Synthesis and antiviral activity of 2′-deoxy-2′-fluoro-2′-C-methyl purine nucleosides as inhibitors of hepatitis C virus RNA replication [J].

Clark, JL ;

Mason, JC ;

Hollecker, L ;

Stuyver, LJ ;

Tharnish, PM ;

McBrayer, TR ;

Otto, MJ ;

Furman, PA ;

Schinazi, RF ;

Watanabe, KA .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (06) :1712-1715

[10] Design, synthesis, and antiviral activity of 2′-deoxy-2′-fluoro-2′-C-methylcytidine, a potent inhibitor of hepatitis C virus replication [J].

Clark, JL ;

Hollecker, L ;

Mason, JC ;

Stuyver, LJ ;

Tharnish, PM ;

Lostia, S ;

McBrayer, TR ;

Schinazi, RF ;

Watanabe, KA ;

Otto, MJ ;

Furman, PA ;

Stec, WJ ;

Patterson, SE ;

Pankiewiez, KW .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (17) :5504-5508

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