BIOMAT Database Logo BIOMAT Database Logo

Design, synthesis, and antiviral properties of 4'-substituted ribonucleosides as inhibitors of hepatitis C virus replication: the discovery of R1479. 2007

David B Smith, and Joseph A Martin, and Klaus Klumpp, and Stewart J Baker, and Peter A Blomgren, and Rene Devos, and Caroline Granycome, and Julie Hang, and Christopher J Hobbs, and Wen-Rong Jiang, and Carl Laxton, and Sophie Le Pogam, and Vincent Leveque, and Han Ma, and Graham Maile, and John H Merrett, and Arkadius Pichota, and Keshab Sarma, and Mark Smith, and Steven Swallow, and Julian Symons, and David Vesey, and Isabel Najera, and Nick Cammack
Medicinal Chemistry, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. Dave.Smith@Roche.com

A series of 4'-substituted ribonucleoside derivatives has been prepared and evaluated for inhibition of hepatitis C virus (HCV) RNA replication in cell culture. The most potent and non-cytotoxic derivative was compound 28 (4'-azidocytidine, R1479) with an IC(50) of 1.28 microM in the HCV replicon system. The triphosphate of compound 28 was prepared and shown to be an inhibitor of RNA synthesis mediated by NS5B (IC(50)=320 nM), the RNA polymerase encoded by HCV. Data on related analogues have been used to generate some preliminary requirements for activity within this series of nucleosides.

UI MeSH Term Description Entries
D008956 Models, Chemical Theoretical representations that simulate the behavior or activity of chemical processes or phenomena; includes the use of mathematical equations, computers, and other electronic equipment. Chemical Models,Chemical Model,Model, Chemical
D008968 Molecular Conformation The characteristic three-dimensional shape of a molecule. Molecular Configuration,3D Molecular Structure,Configuration, Molecular,Molecular Structure, Three Dimensional,Three Dimensional Molecular Structure,3D Molecular Structures,Configurations, Molecular,Conformation, Molecular,Conformations, Molecular,Molecular Configurations,Molecular Conformations,Molecular Structure, 3D,Molecular Structures, 3D,Structure, 3D Molecular,Structures, 3D Molecular
D009705 Nucleosides Purine or pyrimidine bases attached to a ribose or deoxyribose. (From King & Stansfield, A Dictionary of Genetics, 4th ed) Nucleoside,Nucleoside Analog,Nucleoside Analogs,Analog, Nucleoside,Analogs, Nucleoside
D002626 Chemistry, Pharmaceutical Chemistry dealing with the composition and preparation of agents having PHARMACOLOGIC ACTIONS or diagnostic use. Medicinal Chemistry,Chemistry, Pharmaceutic,Pharmaceutic Chemistry,Pharmaceutical Chemistry,Chemistry, Medicinal
D003562 Cytidine A pyrimidine nucleoside that is composed of the base CYTOSINE linked to the five-carbon sugar D-RIBOSE. Cytosine Ribonucleoside,Cytosine Riboside,Ribonucleoside, Cytosine,Riboside, Cytosine
D004353 Drug Evaluation, Preclinical Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications. Drug Screening,Evaluation Studies, Drug, Pre-Clinical,Drug Evaluation Studies, Preclinical,Drug Evaluations, Preclinical,Evaluation Studies, Drug, Preclinical,Evaluation, Preclinical Drug,Evaluations, Preclinical Drug,Medicinal Plants Testing, Preclinical,Preclinical Drug Evaluation,Preclinical Drug Evaluations,Drug Screenings,Screening, Drug,Screenings, Drug
D000998 Antiviral Agents Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. Antiviral,Antiviral Agent,Antiviral Drug,Antivirals,Antiviral Drugs,Agent, Antiviral,Agents, Antiviral,Drug, Antiviral,Drugs, Antiviral
D012263 Ribonucleosides Nucleosides in which the purine or pyrimidine base is combined with ribose. (Dorland, 28th ed)
D012313 RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. (Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed) RNA, Non-Polyadenylated,Ribonucleic Acid,Gene Products, RNA,Non-Polyadenylated RNA,Acid, Ribonucleic,Non Polyadenylated RNA,RNA Gene Products,RNA, Non Polyadenylated
D014529 Uridine A ribonucleoside in which RIBOSE is linked to URACIL. Allo-Uridine,Allouridine,Allo Uridine

Related Publications

David B Smith, and Joseph A Martin, and Klaus Klumpp, and Stewart J Baker, and Peter A Blomgren, and Rene Devos, and Caroline Granycome, and Julie Hang, and Christopher J Hobbs, and Wen-Rong Jiang, and Carl Laxton, and Sophie Le Pogam, and Vincent Leveque, and Han Ma, and Graham Maile, and John H Merrett, and Arkadius Pichota, and Keshab Sarma, and Mark Smith, and Steven Swallow, and Julian Symons, and David Vesey, and Isabel Najera, and Nick Cammack
Design and synthesis of imidazole N-H substituted amide prodrugs as inhibitors of hepatitis C virus replication.
August 2015, Bioorganic & medicinal chemistry letters,
David B Smith, and Joseph A Martin, and Klaus Klumpp, and Stewart J Baker, and Peter A Blomgren, and Rene Devos, and Caroline Granycome, and Julie Hang, and Christopher J Hobbs, and Wen-Rong Jiang, and Carl Laxton, and Sophie Le Pogam, and Vincent Leveque, and Han Ma, and Graham Maile, and John H Merrett, and Arkadius Pichota, and Keshab Sarma, and Mark Smith, and Steven Swallow, and Julian Symons, and David Vesey, and Isabel Najera, and Nick Cammack
Discovery and characterization of substituted diphenyl heterocyclic compounds as potent and selective inhibitors of hepatitis C virus replication.
April 2008, Antimicrobial agents and chemotherapy,
David B Smith, and Joseph A Martin, and Klaus Klumpp, and Stewart J Baker, and Peter A Blomgren, and Rene Devos, and Caroline Granycome, and Julie Hang, and Christopher J Hobbs, and Wen-Rong Jiang, and Carl Laxton, and Sophie Le Pogam, and Vincent Leveque, and Han Ma, and Graham Maile, and John H Merrett, and Arkadius Pichota, and Keshab Sarma, and Mark Smith, and Steven Swallow, and Julian Symons, and David Vesey, and Isabel Najera, and Nick Cammack
Structure-activity relationship of heterobase-modified 2'-C-methyl ribonucleosides as inhibitors of hepatitis C virus RNA replication.
October 2004, Journal of medicinal chemistry,
David B Smith, and Joseph A Martin, and Klaus Klumpp, and Stewart J Baker, and Peter A Blomgren, and Rene Devos, and Caroline Granycome, and Julie Hang, and Christopher J Hobbs, and Wen-Rong Jiang, and Carl Laxton, and Sophie Le Pogam, and Vincent Leveque, and Han Ma, and Graham Maile, and John H Merrett, and Arkadius Pichota, and Keshab Sarma, and Mark Smith, and Steven Swallow, and Julian Symons, and David Vesey, and Isabel Najera, and Nick Cammack
Structure-based discovery of pyrazolobenzothiazine derivatives as inhibitors of hepatitis C virus replication.
March 2013, Journal of medicinal chemistry,
David B Smith, and Joseph A Martin, and Klaus Klumpp, and Stewart J Baker, and Peter A Blomgren, and Rene Devos, and Caroline Granycome, and Julie Hang, and Christopher J Hobbs, and Wen-Rong Jiang, and Carl Laxton, and Sophie Le Pogam, and Vincent Leveque, and Han Ma, and Graham Maile, and John H Merrett, and Arkadius Pichota, and Keshab Sarma, and Mark Smith, and Steven Swallow, and Julian Symons, and David Vesey, and Isabel Najera, and Nick Cammack
Cyclic monophosphate prodrugs of base-modified 2'-C-methyl ribonucleosides as potent inhibitors of hepatitis C virus RNA replication.
May 2007, Bioorganic & medicinal chemistry letters,
David B Smith, and Joseph A Martin, and Klaus Klumpp, and Stewart J Baker, and Peter A Blomgren, and Rene Devos, and Caroline Granycome, and Julie Hang, and Christopher J Hobbs, and Wen-Rong Jiang, and Carl Laxton, and Sophie Le Pogam, and Vincent Leveque, and Han Ma, and Graham Maile, and John H Merrett, and Arkadius Pichota, and Keshab Sarma, and Mark Smith, and Steven Swallow, and Julian Symons, and David Vesey, and Isabel Najera, and Nick Cammack
Hepatitis C virus NS5A replication complex inhibitors: the discovery of daclatasvir.
March 2014, Journal of medicinal chemistry,
David B Smith, and Joseph A Martin, and Klaus Klumpp, and Stewart J Baker, and Peter A Blomgren, and Rene Devos, and Caroline Granycome, and Julie Hang, and Christopher J Hobbs, and Wen-Rong Jiang, and Carl Laxton, and Sophie Le Pogam, and Vincent Leveque, and Han Ma, and Graham Maile, and John H Merrett, and Arkadius Pichota, and Keshab Sarma, and Mark Smith, and Steven Swallow, and Julian Symons, and David Vesey, and Isabel Najera, and Nick Cammack
Discovery and development of hepatitis C virus NS5A replication complex inhibitors.
March 2014, Journal of medicinal chemistry,
David B Smith, and Joseph A Martin, and Klaus Klumpp, and Stewart J Baker, and Peter A Blomgren, and Rene Devos, and Caroline Granycome, and Julie Hang, and Christopher J Hobbs, and Wen-Rong Jiang, and Carl Laxton, and Sophie Le Pogam, and Vincent Leveque, and Han Ma, and Graham Maile, and John H Merrett, and Arkadius Pichota, and Keshab Sarma, and Mark Smith, and Steven Swallow, and Julian Symons, and David Vesey, and Isabel Najera, and Nick Cammack
Discovery of novel P2 substituted 4-biaryl proline inhibitors of hepatitis C virus NS3 serine protease.
August 2013, Bioorganic & medicinal chemistry letters,
David B Smith, and Joseph A Martin, and Klaus Klumpp, and Stewart J Baker, and Peter A Blomgren, and Rene Devos, and Caroline Granycome, and Julie Hang, and Christopher J Hobbs, and Wen-Rong Jiang, and Carl Laxton, and Sophie Le Pogam, and Vincent Leveque, and Han Ma, and Graham Maile, and John H Merrett, and Arkadius Pichota, and Keshab Sarma, and Mark Smith, and Steven Swallow, and Julian Symons, and David Vesey, and Isabel Najera, and Nick Cammack
C-6 aryl substituted 4-quinolone-3-carboxylic acids as inhibitors of hepatitis C virus.
August 2012, Bioorganic & medicinal chemistry,
David B Smith, and Joseph A Martin, and Klaus Klumpp, and Stewart J Baker, and Peter A Blomgren, and Rene Devos, and Caroline Granycome, and Julie Hang, and Christopher J Hobbs, and Wen-Rong Jiang, and Carl Laxton, and Sophie Le Pogam, and Vincent Leveque, and Han Ma, and Graham Maile, and John H Merrett, and Arkadius Pichota, and Keshab Sarma, and Mark Smith, and Steven Swallow, and Julian Symons, and David Vesey, and Isabel Najera, and Nick Cammack
The design, synthesis and biological evaluations of C-6 or C-7 substituted 2-hydroxyisoquinoline-1,3-diones as inhibitors of hepatitis C virus.
January 2012, Bioorganic & medicinal chemistry,
Copied contents to your clipboard!