Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
Add more filters










Publication year range
1.
Bioorg Med Chem Lett ; 27(18): 4323-4330, 2017 09 15.
Article in English | MEDLINE | ID: mdl-28835346

ABSTRACT

Herein we describe the discovery of IDX21437 35b, a novel RPd-aminoacid-based phosphoramidate prodrug of 2'-α-chloro-2'-ß-C-methyluridine monophosphate. Its corresponding triphosphate 6 is a potent inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRp). Despite showing very weak activity in the in vitro Huh-7 cell based HCV replicon assay, 35b demonstrated high levels of active triphosphate 6 in mouse liver and human hepatocytes. A biochemical study revealed that the metabolism of 35b was mainly attributed to carboxyesterase 1 (CES1), an enzyme which is underexpressed in HCV Huh-7-derived replicon cells. Furthermore, due to its metabolic activation, 35b was efficiently processed in liver cells compared to other cell types, including human cardiomyocytes. The selected RP diastereoisomeric configuration of 35b was assigned by X-ray structural determination. 35b is currently in Phase II clinical trials for the treatment of HCV infection.


Subject(s)
Antiviral Agents/pharmacology , DNA-Directed RNA Polymerases/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/pharmacology , Hepacivirus/drug effects , Uridine Monophosphate/analogs & derivatives , Uridine/pharmacology , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , DNA-Directed RNA Polymerases/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hepacivirus/enzymology , Hepatocytes/drug effects , Hepatocytes/virology , Humans , Liver/drug effects , Liver/virology , Mice , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Uridine/chemical synthesis , Uridine/chemistry , Uridine Monophosphate/chemical synthesis , Uridine Monophosphate/chemistry , Uridine Monophosphate/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism
2.
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
3.
Bioorg Med Chem Lett ; 26(18): 4536-4541, 2016 09 15.
Article in English | MEDLINE | ID: mdl-27520942

ABSTRACT

The 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 Letter describes the discovery of a new family of HCV NS5B non-nucleoside inhibitors, based on the bioisosterism between amide and phosphonamidate functions. As part of this program, SAR in this new series led to the identification of IDX17119, a potent non-nucleoside inhibitor, active on the genotypes 1b, 2a, 3a and 4a. The structure and binding domain of IDX17119 were confirmed by X-ray co-crystallization study.


Subject(s)
Antiviral Agents/pharmacology , Genotype , Hepacivirus/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , Allosteric Site , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Crystallography, X-Ray , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolism
4.
Carbohydr Res ; 344(4): 448-53, 2009 Mar 10.
Article in English | MEDLINE | ID: mdl-19147123

ABSTRACT

The first example of a nucleoside analogue bearing a 5'-deoxy-beta-D-allo-septanose as a seven-membered ring sugar moiety, namely 9-(5-deoxy-beta-D-allo-septanosyl)-adenine, is reported. This compound was synthesized in 14 steps from the commercially available D-glycero-D-gulo-1,4-lactone. When evaluated in cell culture experiments against a broad range of viruses, it did not exhibit any significant antiviral effect or cytotoxicity.


Subject(s)
Nucleosides/chemistry , Nucleosides/chemical synthesis , Oligosaccharides/chemistry , Oligosaccharides/chemical synthesis , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Flavivirus/drug effects , Hepacivirus/drug effects , Models, Chemical , Molecular Structure , Nucleosides/pharmacology , Pestivirus/drug effects
7.
Nucleic Acids Symp Ser (Oxf) ; (52): 617-8, 2008.
Article in English | MEDLINE | ID: mdl-18776531

ABSTRACT

A series of novel 4-fluoro-1H-pyrazole-3-carboxamide nucleoside analogues were synthesized and evaluated as potential inhibitors of RNA virus replication, including hepatitis C virus (HCV).


Subject(s)
Antiviral Agents/chemical synthesis , Ribavirin/analogs & derivatives , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Hepacivirus/drug effects
8.
Nucleosides Nucleotides Nucleic Acids ; 26(10-12): 1431-4, 2007.
Article in English | MEDLINE | ID: mdl-18066799

ABSTRACT

In search for new antiviral agents, we have been interested in 1'-C-fluoromethyl branched ribonucleosides. In this paper, we describe the synthesis of 1'-C-fluoromethyladenosine via electrophilic fluorination of exo-glycal.


Subject(s)
Adenosine/analogs & derivatives , Antiviral Agents/chemical synthesis , Adenosine/chemical synthesis , Adenosine/chemistry
9.
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
10.
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
...