Conjugate addition of 2-(bromomethyl)- and 2-(2-bromoethyl)piperidine to alkyl acrylates : application towards the synthesis of 2-(methoxycarbonyl)indolizidine

Conjugate addition of 2-(bromomethyl)- and 2-(2-bromoethyl)piperidine hydrobromide to methyl and ethyl acrylate in the presence of triethylamine afforded the corresponding 3-[2-(bromomethyl)piperidin-1-yl]propanoates and 3-[2-(2-bromoethyl)piperidin-1-yl]propanoates for the first time. Furthermore, methyl 3-[2-(bromomethyl)piperidin-1-yl]propanoate was converted into the novel 2-(methoxycarbonyl)indolizidine upon treatment with lithium diisopropylamide in THF. The latter ester was easily reduced by means of lithium aluminium hydride in diethyl ether, affording 2-(hydroxymethyl)indolizidine in high yield

Identification of Z-Tyr-Ala-CHN 2, a Cathepsin L Inhibitor with Broad-Spectrum Cell-Specific Activity against Coronaviruses, including SARS-CoV-2.

The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is partly under control by vaccination. However, highly potent and safe antiviral drugs for SARS-CoV-2 are still needed to avoid development of severe COVID-19. We report the discovery of a small molecule, Z-Tyr-Ala-CHN 2, which was identified in a cell-based antiviral screen. The molecule exerts sub-micromolar antiviral activity against SARS-CoV-2, SARS-CoV-1, and human coronavirus 229E. Time-of-addition studies reveal that Z-Tyr-Ala-CHN 2 acts at the early phase of the infection cycle, which is in line with the observation that the molecule inhibits cathepsin L. This results in antiviral activity against SARS-CoV-2 in VeroE6, A549-hACE2, and HeLa-hACE2 cells, but not in Caco-2 cells or primary human nasal epithelial cells since the latter two cell types also permit entry via transmembrane protease serine subtype 2 (TMPRSS2). Given their cell-specific activity, cathepsin L inhibitors still need to prove their value in the clinic; nevertheless, the activity profile of Z-Tyr-Ala-CHN 2 makes it an interesting tool compound for studying the biology of coronavirus entry and replication

La solution des problèmes démographiques de la médecine générale française peut-elle s'inspirer des évolutions du système de soins primaires anglais ? (comment peut-on s'inspirer du système britannique pour rendre la médecine générale plus attractive en France ?)

LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Identification of novel Multidrug Resistance-Associated Protein-3 (MRP3) inhibitors in rat and human hepatocytes in suspension

status: publishe

Impact of selection bias on the evaluation of clusters of chemical compounds in the drug discovery process

Abstract Expert opinion plays an important role when selecting promising clusters of chemical compounds in the drug discovery process. Indeed, experts can qualitatively assess the potential of each cluster and, with appropriate statistical methods, these qualitative assessments can be quantified into a success probability for each of them. However, one crucial element often overlooked is the procedure by which the clusters are assigned/selected to/by the experts for evaluation. In the present work, the impact is studied that such a procedure may have on the statistical analysis and the entire evaluation process. It has been shown that some implementations of the selection procedure may seriously compromise the validity of the evaluation and, consequently, the fully random allocation of the clusters to the experts is strongly advocated

Identification and computational modeling of novel Multidrug Resistance-Associated Protein-3 (MRP3) inhibitors in rat and human hepatocytes

status: publishe

A new modeling approach for quantifying expert opinion in the drug discovery process

Expert opinion plays an important role when choosing clusters of chemical compounds for further investigation. Often, the process by which the clusters are assigned to the experts for evaluation, the so-called selection process, and the qualitative ratings given by the experts to the clusters (chosen/not chosen) need to be jointly modeled to avoid bias. This approach is referred to as the joint modeling approach. However, misspecifying the selection model may impact the estimation and inferences on parameters in the rating model, which are of most scientific interest. We propose to incorporate the selection process into the analysis by adding a new set of random effects to the rating model and, in this way, avoid the need to model it parametrically. This approach is referred to as the combined model approach. Through simulations, the performance of the combined and joint models was compared in terms of bias and confidence interval coverage. The estimates from the combined model were nearly unbiased, and the derived confidence intervals had coverage probability around 95% in all scenarios considered. In contrast, the estimates from the joint model were severely biased under some form of misspecification of the selection model, and fitting the model was often numerically challenging. The results show that the combined model may offer a safer alternative on which to base inferences when there are doubts about the validity of the selection model. Importantly, thanks to its greater numerical stability, the combined model may outperform the joint model even when the latter is correctly specified. Copyright © 2015 John Wiley & Sons, Ltd.published_online: 2015-01-30status: publishe

A PERMUTATIONAL-SPLITTING SAMPLE PROCEDURE TO QUANTIFY EXPERT OPINION ON CLUSTERS OF CHEMICAL COMPOUNDS USING HIGH-DIMENSIONAL DATA

© Institute of Mathematical Statistics, 2014. Expert opinion plays an important role when selecting promising clusters of chemical compounds in the drug discovery process. We propose a method to quantify these qualitative assessments using hierarchical models. However, with the most commonly available computing resources, the high dimensionality of the vectors of fixed effects and correlated responses renders maximum likelihood unfeasible in this scenario. We devise a reliable procedure to tackle this problem and show, using theoretical arguments and simulations, that the new methodology compares favorably with maximum likelihood, when the latter option is available. The approach was motivated by a case study, which we present and analyze.Published in at http://dx.doi.org/10.1214/14-AOAS772 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org)status: publishe

Impact of selection bias on the evaluation of clusters of chemical compounds in the drug discovery process

Expert opinion plays an important role when selecting promising clusters of chemical compounds in the drug discovery process. Indeed, experts can qualitatively assess the potential of each cluster, and with appropriate statistical methods, these qualitative assessments can be quantified into a success probability for each of them. However, one crucial element often overlooked is the procedure by which the clusters are assigned to/selected by the experts for evaluation. In the present work, the impact such a procedure may have on the statistical analysis and the entire evaluation process is studied. It has been shown that some implementations of the selection procedure may seriously compromise the validity of the evaluation even when the rating and selection processes are independent. Consequently, the fully random allocation of the clusters to the experts is strongly advocated. Copyright © 2014 John Wiley & Sons, Ltd.status: publishe

Mutations du foncier agricole en frange urbaine : élaboration et mise à l'épreuve d'une politique de régulation territoriale

National audienceLe pôle urbain de Montpellier s’est largement étalé lors des dernières décennies à la faveur de son dynamisme démographique et du retrait de la viticulture : la « maîtrise » communale de l’urbanisme s’est traduite par une urbanisation tous azimuts. Comment mettre fin à ces processus sans compromettre l’économie résidentielle ? C’est une priorité de la nouvelle intercommunalité dont la politique d’aménagement est analysée. La genèse de cette politique est retracée ainsi que sa traduction dans le schéma de cohérence territoriale, dont les objectifs d’économie d’espace et les outils - identification des limites, densification, maîtrise foncière - sont détaillés. Sa mise en oeuvre au niveau communal révèle les forces et les faiblesses de cette politique. Cette étude empirique soutient une réflexion plus générale sur les dynamiques foncières périurbaines et les outils politiques de régulation, à la croisée des problématiques de gouvernance territoriale et de préservation des ressources