Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 9 de 9
Filter
Add more filters










Database
Language
Publication year range
1.
Bioorg Med Chem Lett ; 27(11): 2634-2640, 2017 06 01.
Article in English | MEDLINE | ID: mdl-28416131

ABSTRACT

Hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells, and as a consequence is an attractive target for selective inhibition. This paper describes the discovery of a novel family of HCV NS5B non-nucleoside inhibitors inspired by the bioisosterism between sulfonamide and phosphonamide. Systematic structural optimization in this new series led to the identification of IDX375, a potent non-nucleoside inhibitor that is selective for genotypes 1a and 1b. The structure and binding domain of IDX375 were confirmed by X-ray co-crystalisation study.


Subject(s)
Antiviral Agents/chemistry , Hepacivirus/enzymology , Lactams/chemistry , Organophosphorus Compounds/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Allosteric Regulation , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Binding Sites , Crystallography, X-Ray , Genotype , Half-Life , Haplorhini , Hepacivirus/genetics , Hepacivirus/physiology , Humans , Lactams/pharmacology , Mice , Molecular Dynamics Simulation , Organophosphorus Compounds/pharmacology , Protein Structure, Tertiary , Rats , Structure-Activity Relationship , Sulfonamides/chemistry , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects
2.
Future Med Chem ; 7(13): 1675-700, 2015.
Article in English | MEDLINE | ID: mdl-26424162

ABSTRACT

BACKGROUND: Ribonucleoside analogs possessing a ß-methyl substituent at the 2'-position of the d-ribose moiety have been previously discovered to be potent and selective inhibitors of hepatitis C virus (HCV) replication, their triphosphates acting as alternative substrate inhibitors of the HCV RdRp NS5B. Results/methodology: In this article, the authors detail the synthesis, anti-HCV evaluation in cell-based replicon assays and structure-activity relationships of several phosphoramidate diester derivatives of 2'-C-methylguanosine (2'-MeG). CONCLUSION: The most promising compound, namely the O-[S-(hydroxyl)pivaloyl-2-thioethyl]{abbreviated as O-[(HO)tBuSATE)]} N-benzylamine phosphoramidate diester derivative (IDX184), was selected for further in vivo studies, and was the first clinical pronucleotide evaluated for the treatment of chronic hepatitis C up to Phase II trials.


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Drug Discovery , Guanosine Monophosphate/analogs & derivatives , Hepacivirus/drug effects , Hepatitis C/drug therapy , Guanosine Monophosphate/chemical synthesis , Guanosine Monophosphate/pharmacology , Humans , Structure-Activity Relationship
3.
Org Biomol Chem ; 10(17): 3448-54, 2012 May 07.
Article in English | MEDLINE | ID: mdl-22434259

ABSTRACT

A 6-step procedure was developed for the synthesis of a new family of acyclic nucleoside phosphonates (ANPs), "PHEEPA" [(2-pyrimidinyl-2-(2-hydroxyethoxy)ethyl)phosphonic acids] in overall yields ranging from 4.5% to 32%. These compounds, which possess on one side a hydroxy function and on the other side a phosphonate group, can be considered either as potential antiviral agents or as transition state analogues of nucleoside phosphorylases such as thymidine phosphorylase.


Subject(s)
Biomimetic Materials/chemistry , Biomimetic Materials/chemical synthesis , Chemistry Techniques, Synthetic/methods , Nucleosides/chemistry , Organophosphonates/chemistry , Organophosphonates/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/chemical synthesis , Thymidine Phosphorylase/chemistry
4.
Bioorg Med Chem ; 17(6): 2321-6, 2009 Mar 15.
Article in English | MEDLINE | ID: mdl-19254848

ABSTRACT

Several thieno[3,4-d]pyrimidine derivatives, including four hitherto unknown 2',3'-dideoxy- and 2',3'-dideoxy-2',3'-didehydro-C-nucleoside analogues of adenosine and inosine have been synthesized. When evaluated in cell culture experiments against human immunodeficiency virus, none of the tested compounds exhibited any significant antiviral effect, while two of them showed some cytotoxicity.


Subject(s)
Adenosine/analogs & derivatives , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Inosine/analogs & derivatives , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Antiviral Agents/chemistry , HIV/drug effects , Magnetic Resonance Spectroscopy , Pyrimidines/chemistry , Spectrometry, Mass, Electrospray Ionization
6.
Antivir Chem Chemother ; 18(4): 225-42, 2007.
Article in English | MEDLINE | ID: mdl-17907380

ABSTRACT

RNA viruses are the agents of numerous widespread and often severe diseases. Their unique RNA-dependent RNA polymerase (RDRP) is essential for replication and, thus, constitutes a valid target for the development of selective chemotherapeutic agents. In this regard, we have investigated sugar-modified ribonucleoside analogues as potential inhibitors of the RDRP. Title compounds retain 'natural' pyrimidine bases, but possess a beta-methyl substituent at the 2'-position of the D- or L-ribose moiety. Evaluation against a broad range of RNA viruses, either single-stranded positive (ssRNA+), single-stranded negative (ssRNA-) or double-stranded (dsRNA), revealed potent activities for D-2'-C-methyl-cytidine and -uridine against ssRNA+, and dsRNA viruses. None of the L-enantiomers were active. Moreover, the 5'-triphosphates of the active D-enantiomers were found to inhibit the bovine virus diarrhoea virus polymerase. Thus, the 2'-methyl branching of natural pyrimidine ribonucleosides transforms physiological molecules into potent, broad-spectrum antiviral agents that merit further development.


Subject(s)
Antiviral Agents/pharmacology , Pyrimidine Nucleosides/pharmacology , RNA Viruses/drug effects , RNA Viruses/physiology , Virus Replication/drug effects , Animals , Antiviral Agents/chemistry , Cell Line , Cricetinae , Dogs , Haplorhini , Humans , Molecular Structure , Pyrimidine Nucleosides/chemistry , Structure-Activity Relationship
7.
J Med Chem ; 49(22): 6614-20, 2006 Nov 02.
Article in English | MEDLINE | ID: mdl-17064080

ABSTRACT

In our search for new therapeutic agents against chronic hepatitis C, a ribonucleoside analogue, 2'-C-methylcytidine, was discovered to be a potent and selective inhibitor in cell culture of a number of RNA viruses, including the pestivirus bovine viral diarrhea virus, a surrogate model for hepatitis C virus (HCV), and three flaviviruses, namely, yellow fever virus, West Nile virus, and dengue-2 virus. However, pharmacokinetic studies revealed that 2'-C-methylcytidine suffers from a low oral bioavailability. To overcome this limitation, we have synthesized the 3'-O-l-valinyl ester derivative (dihydrochloride form, valopicitabine, NM283) of 2'-C-methylcytidine. We detail herein for the first time the chemical synthesis and physicochemical characteristics of this anti-HCV prodrug candidate, as well as a comparative study of its pharmacokinetic parameters with those of its parent nucleoside analogue, 2'-C-methylcytidine.


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Cytidine/analogs & derivatives , Hepacivirus/drug effects , Prodrugs/chemical synthesis , Prodrugs/pharmacokinetics , Pyrimidine Nucleosides/chemical synthesis , Pyrimidine Nucleosides/pharmacokinetics , Animals , Biological Availability , Chemical Phenomena , Chemistry, Physical , Chromatography, High Pressure Liquid , Cytidine/chemistry , Cytosol/metabolism , Humans , Liver/metabolism , Magnetic Resonance Spectroscopy , Protein Binding , Rats , Rats, Sprague-Dawley , Solubility
8.
Curr Protoc Nucleic Acid Chem ; Chapter 14: Unit 14.3, 2006 Apr.
Article in English | MEDLINE | ID: mdl-18428950

ABSTRACT

The "unnatural" l-nucleoside beta-l-2'-deoxythymidine (L-dT) is a potent, specific, and selective inhibitor of the replication of hepatitis B virus (HBV), which is currently in Phase III clinical trials. This unit describes, in detail, a semi-large-scale synthesis of l-dT. This convenient methodology produces l-dT in six steps starting with l-ribose and ending with a satisfactory overall yield of l-dT, and may be applied to other 2'-deoxynucleosides, incorporating different heterocyclic bases.


Subject(s)
Antiviral Agents/chemical synthesis , Thymidine/chemical synthesis , Antiviral Agents/pharmacology , Hepatitis B virus/drug effects , Hepatitis B virus/physiology , Thymidine/pharmacology , Virus Replication/drug effects
9.
Antivir Chem Chemother ; 15(5): 269-79, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15535049

ABSTRACT

beta-L-2'-Deoxycytidine (beta-L-dC) is a potent, selective and specific anti-hepatitis B virus (HBV) agent. To improve its oral bioavailability, several derivatives involving sugar or base acylation, as well N4-derivatization with an N,N-(dimethylamino)methylene function, were synthesized. The physicochemical characteristics (including chemical stabilities, solubilities and distribution coefficient values) and pharmacokinetics of these compounds were determined and compared with those of the parent drug, beta-L-dC.


Subject(s)
Antiviral Agents/chemical synthesis , Deoxycytidine/analogs & derivatives , Deoxycytidine/chemical synthesis , Hepatitis B virus/drug effects , Prodrugs/chemical synthesis , Acylation , Administration, Oral , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Biological Availability , Deoxycytidine/pharmacokinetics , Deoxycytidine/pharmacology , Haplorhini , Hepatitis B virus/metabolism , Microbial Sensitivity Tests , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Solubility
SELECTION OF CITATIONS
SEARCH DETAIL
...