RESUMEN
Lead Diversification is a new technology platform developed at Pfizer for the functionalization of drug molecules using C-H activation. We describe its application to some drug programs such as P38 and gMTP and the development of some new plate based screens including a fluorination screen.
Asunto(s)
Acetilmuramil-Alanil-Isoglutamina/farmacología , Compuestos Organometálicos/farmacología , Paladio/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Acetilmuramil-Alanil-Isoglutamina/análogos & derivados , Acetilmuramil-Alanil-Isoglutamina/química , Humanos , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Properties-retention studies were undertaken on a test library of sulfonamides using supercritical fluid chromatography with CO(2)-MeOH mobile phases (in the presence or absence of additive) and a 2-ethyl-pyridyl column. Taking a restricted range of retention ratios, k (1
Asunto(s)
Cromatografía con Fluido Supercrítico/métodos , Sulfonamidas/análisis , Algoritmos , Estructura Molecular , Análisis de Regresión , Sulfonamidas/químicaRESUMEN
The enantiomeric separation of a series of 2-arylindoles, developed as 5HT(2A) receptor antagonists for the treatment of schizophrenia, was investigated. Evaluation of a number of chiral stationary phases (CSPs) suggested that Chiralcel OD-H and Chiralpak AD were the most versatile for these compounds, and were employed for more detailed studies. A degree of complementarity between the CSPs was observed, such that Chiralcel OD-H was more effective for piperidine-containing molecules and Chiralpak AD for piperazine- and morpholine-containing molecules. The presence of a basic secondary amine was detrimental chromatographically, but resolution was improved substantially by employing diethylamine (DEA) in the mobile phase. All separations were either enthalpy-controlled or showed no temperature dependence. Differential temperature effects between series highlighted the possibility of multiple binding modes on these CSPs. Based on this study, it is possible to make a more rational selection of chromatographic conditions for future novel analogues.
Asunto(s)
Amilosa/análogos & derivados , Carbamatos , Celulosa/análogos & derivados , Cromatografía Líquida de Alta Presión/métodos , Indoles/aislamiento & purificación , Fenilcarbamatos , Cromatografía Líquida de Alta Presión/instrumentación , Indoles/análisis , Indoles/química , Indoles/uso terapéutico , Polisacáridos , Reproducibilidad de los Resultados , Esquizofrenia/tratamiento farmacológico , Sensibilidad y Especificidad , Coloración y Etiquetado/métodos , Estereoisomerismo , TemperaturaRESUMEN
Stationary phase optimized selectivity liquid chromatography (SOSLC) is a promising technique to optimize the selectivity of a given separation by using a combination of different stationary phases. Previous work has shown that SOSLC offers excellent possibilities for method development, especially after the recent modification towards linear gradient SOSLC. The present work is aimed at developing and extending the SOSLC approach towards selectivity optimization and method development for green chromatography. Contrary to current LC practices, a green mobile phase (water/ethanol/formic acid) is hereby preselected and the composition of the stationary phase is optimized under a given gradient profile to obtain baseline resolution of all target solutes in the shortest possible analysis time. With the algorithm adapted to the high viscosity property of ethanol, the principle is illustrated with a fast, full baseline resolution for a randomly selected mixture composed of sulphonamides, xanthine alkaloids and steroids.
Asunto(s)
Cromatografía Liquida/métodos , Tecnología Química Verde/métodos , Modelos Químicos , Algoritmos , Etanol/química , Formiatos/química , Viscosidad , Agua/químicaRESUMEN
The effects of increasing concentrations of ammonium acetate additive in supercritical fluid chromatography were studied on silica, 2-ethyl-pyridine and endcapped 2-ethyl-pyridine stationary phases. The study involved the addition of increasing concentrations of the ammonium acetate either in the mobile phase modifier (methanol) or in the sample solvent. The effects of ammonium acetate on retention and peak shape of the analytes were evaluated. Compounds that exhibited satisfactory chromatographic behaviour in the absence of the additive were virtually unaffected by its presence in the mobile phase or sample solvent. Nevertheless, compounds that exhibited late elution and strongly tailing peak shapes when pure methanol was used showed dramatically improved chromatographic behaviour in the presence of the additive. Shorter retention was observed not only when the modifier was introduced in the mobile phase but also when it was in the sample solvent.
Asunto(s)
Acetatos , Dióxido de Carbono , Cromatografía con Fluido Supercrítico , Metanol , Antiinflamatorios no Esteroideos/análisis , Antihipertensivos/análisis , Atenolol/análisis , Cromatografía Líquida de Alta Presión , Diltiazem/análisis , Espectrometría de Masas , Naproxeno/análisis , Piridinas/química , Dióxido de Silicio/química , Sulfonamidas/análisis , Propiedades de SuperficieRESUMEN
Supercritical fluid chromatography (SFC) is fast becoming a technique of choice for the analysis of a wide range of compounds and has been found to be complementary to high-performance liquid chromatography (HPLC). The combination of SFC and mass spectrometry (MS) affords a very useful tool in the separation and analysis of compounds. In this study the ionisation of samples in the absence of an applied electrospray voltage has been observed when using SFC/MS, with some compounds showing increased sensitivity when all ionisation source high voltage (HV) is removed. In an attempt to understand the mechanism of ionisation, a series of test compounds were analysed using standard electrospray ionisation (ESI) and atmospheric pressure chemical ionisation (APCI) source configurations and also different API source designs. In both cases, data were acquired with the applied high voltage on (normal conditions) or with the high voltage off, i.e. no voltage spray (novo-spray). The standards were analysed with a range of pressure and modifier percentage conditions. To understand the nature of the ionisation process observed, this was compared with three established liquid-to-gas ionisation mechanisms. These were thermospray (TSP), charge residue model (CRM) of ESI and sonic spray ionisation (SSI). Experiments were undertaken in an attempt to explain this ionisation phenomenon and quantify any observed change in sensitivity. The most important point to note is that enhanced ionisation was observed under novo-spray conditions in a SFC/MS configuration, which in certain cases provides a lowering in the overall limit of detection (LOD).
Asunto(s)
Cromatografía con Fluido Supercrítico/métodos , Iones/química , Espectrometría de Masa por Ionización de Electrospray/métodosRESUMEN
The protease gamma-secretase plays a pivotal role in the synthesis of pathogenic amyloid-beta in Alzheimer's disease (AD). Here, we report a further extension to a series of cyclohexyl sulfone-based gamma-secretase inhibitors which has allowed the preparation of highly potent compounds which also demonstrate robust Abeta(40) lowering in vivo (e.g., compound 32, MED 1mg/kg p.o. in APP-YAC mice).
Asunto(s)
Ciclohexanos/administración & dosificación , Ciclohexanos/farmacología , Endopeptidasas/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Sulfonas/administración & dosificación , Sulfonas/farmacología , Administración Oral , Secretasas de la Proteína Precursora del Amiloide , Péptidos beta-Amiloides/efectos de los fármacos , Animales , Ácido Aspártico Endopeptidasas , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ciclohexanos/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Ratones , Estructura Molecular , Fragmentos de Péptidos/efectos de los fármacos , Relación Estructura-Actividad , Sulfonas/química , Factores de TiempoRESUMEN
A new synthetic approach to tricyclic pyridones bearing a fused seven-membered ring is described. These compounds exhibit atropisomerism and exist in enantiomeric forms. Chiral HPLC separation of the enantiomers has allowed the rates of racemization to be measured and hence the free energy barrier for flipping the seven-membered ring to be deduced. Introduction of a further element of planar chirality leads to diastereomeric atropisomerism. The rate of interconversion of the diastereomers has been quantified by 2D EXSY NMR spectroscopy allowing a full description of the conformational dynamics of the system.