Kinase-independent phosphoramidate S1P1 receptor agonist benzyl ether derivatives

Previously published S1P receptor modulator benzyl ether derivatives have shown potential as being viable therapeutics for the treatment of neurodegenerative diseases, however, two of the most S1P1-selective compounds are reported as being poorly phosphorylated by kinases in vivo. Phosphoramidates of BED compounds (2a, 2b) were synthesised with the aim of producing kinase-independent S1P receptor modulators. Carboxypeptidase, human serum and cell lysate processing experiments were conducted. ProTide BED analogues were found to have an acceptable level of stability in acidic and basic conditions and in vitro metabolic processing experiments showed that they are processed to the desired pharmacologically active monophosphate. The research describes the development of an entirely novel family of therapeutic agents

Quantification de l'arginine-vasopressine dans le plasma par spectrométrie de masse en tandem

Développer et optimiser une méthode de dosage de la vasopressine dans le plasma humain depuis le prélèvement sanguin jusqu’à l’analyse en LC-MS/MS en passant par une extraction en phase solide

Phosphonoamidate prodrugs of C5-substituted pyrimidine acyclic nucleosides for antiviral therapy

Acyclic nucleoside phosphonates (ANPs) are nowadays one of the key drugs in the treatment of DNA virus and retrovirus infections. In this work, we report the synthesis and antiviral evaluation of phosphonoamidate and diamidates prodrugs of C5-pyrimidine acyclic nucleosides derivatives functionalized with but-2-enyl- chain. In the phosphonoamidate series, the most active compound 15, showed sub-micromolar activity against varicella zoster virus (VZV) (EC50 =0.09-0.5 μM) and μM activity against human cytomegalovirus (HCMV) and herpes simplex virus (HSV). Separation of single diastereoisomers for compound 14, showed that 14b had better anti-herpesvirus activity and no cytotoxicity compared to the diastereoisomeric mixture 14. Very interestingly, phosphonodiamidate 21 showed anti-herpesvirus activity with excellent activity against wild type and thymidine kinase-deficient (TK-) VZV strains (EC50 = 0.47 and 0.2 μM, respectively) and HCMV (EC50 = 3.5-7.2 μM) without any cytotoxicity (CC50 >100)

Phosphoramidates and phosphonamidates (ProTides) with antiviral activity

Following the first report on the nucleoside phosphoramidate (ProTide) prodrug approach in 1990 by Chris McGuigan, the extensive investigation of ProTide technology has begun in many laboratories. Designed with aim to overcome limitations and the key resistance mechanisms associated with nucleoside analogues used in the clinic (poor cellular uptake, poor conversion to the 5′-monophosphate form), the ProTide approach has been successfully applied to a vast number of nucleoside analogues with antiviral and anticancer activity. ProTides consist of a 5′-nucleoside monophosphate in which the two hydroxyl groups are masked with an amino acid ester and an aryloxy component which once in the cell is enzymatically metabolized to deliver free 5′-monophosphate, which is further transformed to the active 5′-triphosphate form of the nucleoside analogue. In this review, the seminal contribution of Chris McGuigan’s research to this field is presented. His technology proved to be extremely successful in drug discovery and has led to two Food and Drug Administration-approved antiviral agents

Les portefeuilles-titres des résidents français entre 2007 et 2010 d’après les statistiques de détention « titre par titre » de la Banque de France.

À la fin 2010, les résidents français détenaient 5 440 milliards d’euros de titres, soit un encours en légère baisse depuis la fin 2007. De 2007 à 2010, les ménages ont été globalement vendeurs de titres, tandis que les sociétés d’assurance achetaient principalement des valeurs émises par des non-résidents.choix de portefeuille, détention de titres, position extérieure nette, titres de créance, actions, obligations, parts d’OPCVM, résidents, non-résidents, notation, mise en transparence des OPCVM, secteurs institutionnels, catégories socioprofessionnelles, ménages, institutions financières monétaires, sociétés d’assurance, administrations publiques.

La détention par les non-résidents des actions des sociétés françaises du CAC 40 à fin 2010.

En 2010, la part des non-résidents dans le capital des sociétés françaises du CAC 40 (42,4 %) a légèrement baissé (– 2,2 points).Marchés boursiers, investissements de portefeuille, taux de détention, non-résidents, CAC 40.

Symmetrical diamidate prodrugs of nucleotide analogues for drug delivery

The use of pronucleotides to circumvent the well-known drawbacks of nucleotide analogs has played a significant role in the area of antiviral and anticancer drug delivery. Several motifs have been designed to mask the negative charges on the phosphorus moiety of either nucleoside monophosphates or nucleoside phosphonates, in order to increase their hydrophobicity and allow entry of the compound into the cell. Among them the bis-amidate analogs, having two identical amino acids as masking groups through a P–N bond, represent a more recent approach for the delivery of nucleotide analogs, endowed with antiviral or anticancer activity. Different synthetic strategies are commonly used for preparing phosphorodiamidates of nucleosides. In this protocol, we would like to focus on the description of the synthetic methodology that in our hand gave the best results using 2′-3′-didehydro-2′-3′-dideoxythymidine (d4T, Stavudine) as model nucleoside. A second strategy for preparing diamidates of nucleoside phosphonates will be reported using {[2-(6-amino-9 H-purin-9-yl)ethoxy]methyl}phosphonic acid (PMEA, adefovir) as model substrate

La détention par les non-résidents des actions des sociétés françaises du CAC 40 à fin 2008.

À fin 2008, le taux de détention de la capitalisation des sociétés françaises du CAC 40 par les non-résidents recule pour la deuxième année consécutive pour s’établir à 39,2 %, marquant une baisse de deux points par rapport à la fin de l’année 2007.Marchés boursiers, investissements de portefeuille, taux de détention, non-résidents, CAC 40.

Peak acceleration limiter for vibrational tester Patent

Electronic detection system for peak acceleration limits in vibrational testing of spacecraft component