ABSTRACT
Nuclear, radiological, biological and chemical hazards are caused by agents of very different origins. They can be blatant or insidious, difficult to detect, accidental or intentional. In all cases, in addition to treating victims, the aim is to avoid contamination of hospital services. Faced with these risks, which are often seen as unlikely or too complex, the firefighter nurse represents an asset for his or her establishment, in terms of both crisis anticipation and management.
Subject(s)
Firefighters , Nurses , Humans , Chemical Hazard Release , Biohazard Release , Radioactive Hazard ReleaseABSTRACT
The Many Victims plan describes aims to organize evacuations in a coherent manner, to preserve the human and material resources capacity of the fire and rescue service. The aim is to avoid postponing the disaster on the ground to the hospital and to guarantee the continuity of response to the current risk and an over-event. In this device, the firefighter nurse is an asset by his ability to take care of serious victims without the physical presence of a doctor, in a context of crisis.
Subject(s)
Disasters , Humans , HospitalsABSTRACT
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/metabolismABSTRACT
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 RelationshipABSTRACT
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.