Journal ArticleDOI
Discovery of a β-d-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus.
Michael J. Sofia,Donghui Bao,Wonsuk Chang,Jinfa Du,Dhanapalan Nagarathnam,Rachakonda Suguna,P. Ganapati Reddy,Bruce S. Ross,Peiyuan Wang,Hai-Ren Zhang,Shalini Bansal,Christine Espiritu,Meg Keilman,Angela M. Lam,Holly M. Micolochick Steuer,Congrong Niu,Michael J. Otto,Phillip A. Furman +17 more
TLDR
Phosphoramidate prodrugs of the 5'-phosphate derivative of the β-d- 2'-deoxy-2'-α-fluoro-2-β-C-methyluridine nucleoside showed significant potency in the HCV subgenomic replicon assay and produced high levels of triphosphates 6 in primary hepatocytes and in the livers of rats, dogs, and monkeys when administered in vivo.Abstract:
Hepatitis C virus (HCV) is a global health problem requiring novel approaches for effective treatment of this disease. The HCV NS5B polymerase has been demonstrated to be a viable target for the development of HCV therapies. β-d-2′-Deoxy-2′-α-fluoro-2′-β-C-methyl nucleosides are selective inhibitors of the HCV NS5B polymerase and have demonstrated potent activity in the clinic. Phosphoramidate prodrugs of the 5′-phosphate derivative of the β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleoside were prepared and showed significant potency in the HCV subgenomic replicon assay (<1 μM) and produced high levels of triphosphate 6 in primary hepatocytes and in the livers of rats, dogs, and monkeys when administered in vivo. The single diastereomer 51 of diastereomeric mixture 14 was crystallized, and an X-ray structure was determined establishing the phosphoramidate stereochemistry as Sp, thus correlating for the first time the stereochemistry of a phosphoramidate prodrug with biological activity. 51 (PSI-7977...read more
Citations
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Journal ArticleDOI
Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II–III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas
Yu Zhou,Jiang Wang,Zhanni Gu,Shuni Wang,Wei Zhu,José Luis Aceña,Vadim A. Soloshonok,Kunisuke Izawa,Hong Liu +8 more
TL;DR: Compounds Currently in Phase II−III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas is presented.
Journal ArticleDOI
Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design.
TL;DR: In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.
Journal ArticleDOI
Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection
Mark S. Sulkowski,David F. Gardiner,Maribel Rodriguez-Torres,K. Rajender Reddy,Tarek Hassanein,Ira M. Jacobson,Eric Lawitz,Anna S. Lok,Federico Hinestrosa,Paul J. Thuluvath,Howard J. Schwartz,David R. Nelson,Gregory T. Everson,Timothy Eley,Megan Wind-Rotolo,Shu-Pang Huang,Min Gao,Dennis Hernandez,Fiona McPhee,Diane Sherman,R. Hindes,William T. Symonds,Claudio Pasquinelli,Dennis M. Grasela +23 more
TL;DR: Once-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3, including patients with no response to prior therapy with telaprevir or boceprevir.
Nucleotide Polymerase Inhibitor So fos bu vir plus Ribavirin for Hepatitis C
E.J. Gane,Catherine A.M. Stedman,Robert H. Hyland,Xiao Ding,Evguenia S. Svarovskaia,William T. Symonds,R. Hindes,M.M. Berrey +7 more
TL;DR: Sofosbuvir plus ribavirin for 12 weeks may be effective in previously untreated patients with HCV genotype 1, 2, or 3 infection, and the rate of sustained virologic response 24 weeks after therapy is reported.
Journal ArticleDOI
Nucleotide Polymerase Inhibitor Sofosbuvir plus Ribavirin for Hepatitis C
Edward Gane,Catherine A.M. Stedman,Robert H. Hyland,Xiao Ding,Evguenia S. Svarovskaia,William T. Symonds,R. Hindes,M.M. Berrey +7 more
TL;DR: In this paper, the authors evaluated sofosbuvir, an oral nucleotide inhibitor of HCV polymerase, in interferon-sparing and interfon-free regimens for the treatment of hepatitis C virus (HCV) infection.
References
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Journal ArticleDOI
A short history of SHELX
TL;DR: This paper could serve as a general literature citation when one or more of the open-source SH ELX programs (and the Bruker AXS version SHELXTL) are employed in the course of a crystal-structure determination.
Journal ArticleDOI
SIR97: a new tool for crystal structure determination and refinement
Angela Altomare,Maria Cristina Burla,Mercedes Camalli,Giovanni Luca Cascarano,Carmelo Giacovazzo,Antonietta Guagliardi,Anna Moliterni,Giampiero Polidori,Riccardo Spagna +8 more
TL;DR: SIR97 is the integration of two programs, SIR92 and CAOS, the first devoted to the solution of crystal structures by direct methods, the second to refinement via least-squares–Fourier procedures.
Journal ArticleDOI
Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
Michael W. Fried,Mitchell L. Shiffman,K. Rajender Reddy,C. Smith,George Marinos,Fernando L. Gonçales,Dieter Häussinger,Moisés Diago,Giampiero Carosi,Daniel Dhumeaux,Antonio Craxì,A. Lin,Joseph Hoffman,Jian Yu +13 more
TL;DR: In patients with chronic hepatitis C, once-weekly peginterferon alfa-2a plus ribavirin was tolerated as well as interferonAlfa- 2b plus Ribavirin and produced significant improvements in the rate of sustained virologic response, as compared with interfer on alfa -2b plus ribvirin or pegin terferonalfa-3a alone.
Journal ArticleDOI
The global burden of hepatitis C.
TL;DR: The reduction of global mortality and morbidity related to chronic hepatitis C should be a concern to public health authorities, and primary, secondary and tertiary prevention activities should be implemented and monitored in each country, with precise targets set to be reached.
Journal ArticleDOI
Genetic diversity and evolution of hepatitis C virus--15 years on.
TL;DR: Two contrasting aspects of conservatism and adaptability provide a fascinating paradigm in which to explore the complex selection pressures that underlie the evolution of HCV and other persistent viruses.
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