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Understanding compound metabolism in early drug discovery aids medicinal chemistry in designing molecules with improved safety and ADME properties. While advancements in metabolite prediction brings increased confidence, structural decisions require experimental data. In vitro metabolism studies using liquid chromatography and high-resolution mass spectrometry (LC–MS) are generally resource intensive and performed on very few compounds, limiting the chemical space that can be examined.Here, we describe a novel metabolism strategy increasing compound throughput using residual in vitro clearance samples conducted at drug concentrations of 0.5 µM. Analysis by robust ultra high-performance liquid chromatography separation and accurate-mass MS detection ensures major metabolites are identified from a single injection. In silico prediction (parent cLogD) tailors chromatographic conditions, with data-dependent tandem mass spectroscopy targeting predicted metabolites. Software-assisted data mining, structure elucidation and automatic reporting are used.Confidence in the globally aligned workflow is demonstrated with 16 marketed drugs. The approach is now implemented routinely across our laboratories. To date, the success rate for identification of at least one major metabolite is 85%. The utility of these data has been demonstrated across multiple projects, allowing earlier medicinal chemistry decisions to increase efficiency and impact of the design–make–test cycle thus improving the translatability of early in vitro metabolism data. Understanding compound metabolism in early drug discovery aids medicinal chemistry in designing molecules with improved safety and ADME properties. While advancements in metabolite prediction brings increased confidence, structural decisions require experimental data. In vitro metabolism studies using liquid chromatography and high-resolution mass spectrometry (LC–MS) are generally resource intensive and performed on very few compounds, limiting the chemical space that can be examined. Here, we describe a novel metabolism strategy increasing compound throughput using residual in vitro clearance samples conducted at drug concentrations of 0.5 µM. Analysis by robust ultra high-performance liquid chromatography separation and accurate-mass MS detection ensures major metabolites are identified from a single injection. In silico prediction (parent cLogD) tailors chromatographic conditions, with data-dependent tandem mass spectroscopy targeting predicted metabolites. Software-assisted data mining, structure elucidation and automatic reporting are used. Confidence in the globally aligned workflow is demonstrated with 16 marketed drugs. The approach is now implemented routinely across our laboratories. To date, the success rate for identification of at least one major metabolite is 85%. The utility of these data has been demonstrated across multiple projects, allowing earlier medicinal chemistry decisions to increase efficiency and impact of the design–make–test cycle thus improving the translatability of early in vitro metabolism data.

Additional file 2. The percentage of intermediate metabolizers by treatment. The percentage of subjects who were intermediate metabolizers (IM) with error bars representing the standard error of the mean.

SRT2104 is a novel, first-in-class, highly selective small molecule activator of the NAD + dependent deacetylase SIRT1. SRT2104 was dosed to healthy male and female volunteers in a series of phase 1 clinical studies that were designed to elucidate tolerability and pharmacokinetics associated with oral dosing to aid in dose selection for subsequent clinical trials.In the first-in-human study, there was both a single dose phase and 7 day repeat dose phase. Doses used ranged from 0.03 to 3.0 g. A radioactive microtracer study was subsequently conducted to determine systemic clearance, bioavailability and preliminary metabolism, and a crossover study was conducted to determine the effect of gender, formulation and feeding state on SRT2104 pharmacokinetics.SRT2104 was well tolerated in all of these studies, with no serious adverse reactions observed. SRT2104 displayed a dose-dependent, but sub-proportional increase in exposure following single dose and repeated dose administration. Accumulation of three-fold or less occurs after 7 days of repeat dosing. The mean bioavailability was circa 14% and the mean clearance was circa 400 ml min(-1). Although there were no substantial effects on exposure resulting from gender or formulation differences, a notable food effect was observed, manifested as up to four-fold increase in exposure parameters.In the absence of an optimized formulation of SRT2104, the food effect can be used to maximize exposure in future clinical studies. Combined with the good tolerability of all doses demonstrated in these studies, the favourable selectivity profile of SRT2104 allows for the use of this SIRT1 modulator for target validation in the clinic.

Schweizerische Zeitschrift für Bildungswissenschaften 31 (2009) 1, S. 117-134, Cet article concerne l'étude des effets d'un programme de prévention de la violence implanté dans une école spécialisée qui accueille des adolescents présentant de graves troubles du comportement. L'évaluation faite après trois années d'activité du programme démontre une diminution des comportements violents et une amelioration de l'autocontrôle comportemental chez les élèves de cette école. La qualité de la relation maître-élèves, l'importance de la collaboration entre les intervenants, de meme que le niveau d'appropriation du programme par l'équipe scolaire sont aussi des aspects discutés dans cet article. Des perspectives intéressantes concernant le développement des habiletés d'entraide chez des élèves provenant d'un milieu scolaire à très haut degré d'agressivité sont finalement présentées. (DIPF/Orig.), Dieser Beitrag untersucht die Effekte eines Gewaltpräventionsprogramms, das in einer Sonderschule für Jugendliche mit schweren Verhaltensauffälligkeiten umgesetzt wurde. Die Evaluation wurde nach drei Jahren der Programmumsetzung durchgeführt und weist auf eine Reduktion des Gewaltverhaltens und eine Verbesserung der Selbstregulation im Verhalten der Schülerinnen und Schüler hin. Im Beitrag werden zudem die Qualität der Lehrer-Schüler-Beziehung, die Bedeutung der Zusammenarbeit zwischen den Teilnehmenden selber sowie die Kompetenz des Schulteams in der Programmumsetzung diskutiert. Schließlich werden auch interessante Erkenntnisse bezüglich der Hilfsbereitschaft der Kinder in einem Schulklima mit sehr hohem Aggressionsniveau präsentiert. (DIPF/Orig.)