RESUMEN
Starting from a thiazolidin-4-one HTS hit, a novel series of substituted lactams was identified and developed as dual orexin receptor antagonists. In this Letter, we describe our initial efforts towards the improvement of potency and metabolic stability. These investigations delivered optimized lead compounds with CNS drug-like properties suitable for further optimization.
Asunto(s)
Descubrimiento de Drogas , Lactamas/farmacología , Antagonistas de los Receptores de Orexina , Animales , Relación Dosis-Respuesta a Droga , Humanos , Lactamas/química , Lactamas/metabolismo , Estructura Molecular , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Aiming to control neurite formation and navigate the axonal growth by an extrinsic guidance, we report on the design, synthesis and biological evaluation of caged retinoids. Agonists of RARß have been temporarily blocked either by the [(α-methyl-2-nitropiperonyl)oxy]carbonyl (MeNPOC) group or by immobilization using nitrocatechol linkers on TiO2 particles. Release on demand has been achieved by release under UV irradiation, leading to the biologically active compounds, which have been shown to induce neuronal differentiation and neurite outgrowth.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Neuritas/efectos de los fármacos , Fármacos Fotosensibilizantes/farmacología , Retinoides/farmacología , Línea Celular Tumoral , Humanos , Estructura Molecular , Fármacos Fotosensibilizantes/química , Receptores de Ácido Retinoico/agonistas , Retinoides/químicaAsunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Witanólidos/síntesis química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Cristalografía por Rayos X , Humanos , Conformación Molecular , Neuritas/efectos de los fármacos , Neuritas/fisiología , Oxígeno Singlete/química , Estereoisomerismo , Withania/química , Witanólidos/química , Witanólidos/farmacologíaRESUMEN
The first total syntheses of the piericidin related natural products Mer-A2026B and JBIR-02 are reported. Key features of the synthetic approach involve an Ir-catalyzed one-pot C-H activation/oxidation procedure for the preparation of the hydroxypyridine, a vinylogous Mukaiyama aldol reaction, and a final Negishi cross-coupling of an advanced pyridine derivative with an allylic side chain precursor. In addition, the absolute configuration of Mer-A2026B (9R,10R) and JBIR-02 (9R,10R) was established.