RESUMO
Pyridylmethylsulfonamide series were the first reported example of positive allosteric modulators (PAM) of the mGlu2 receptor. The hydroxyacetophenone scaffold is a second series of mGlu2 PAMs we have identified. This series of molecules are potent mGlu2 potentiators and possess significant CysLT1 (cysteinyl leukotriene receptor 1) antagonist activity, showing in vivo efficacy in a dural plasma protein extravasation (PPE) model of migraine. In this paper, we describe the dual SAR, pharmacokinetics and preclinical in vivo efficacy data for a tetrazole containing hydroxyacetophenone scaffold.
Assuntos
Descoberta de Drogas , Transtornos de Enxaqueca/tratamento farmacológico , Receptores de Leucotrienos/metabolismo , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Sulfonamidas/farmacologia , Regulação Alostérica/efeitos dos fármacos , Animais , Cães , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Ratos , Receptores de Glutamato Metabotrópico/agonistas , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/químicaRESUMO
Allylic phosphonium ylides are readily generated by the combination of an allylic alcohol, a carbene, and a chlorophosphite. Here we demonstrate that these intermediates undergo a thermal [3,3]-rearrangement to provide single isomers of homoallylic phosphonates in good to excellent yields. This new reaction manifold for phosphorus ylides is tolerant of a range of substitution patterns on the reactants and provides access to structurally complex intermediates for the synthesis of enzyme inhibitors, aminophosphonic acids, and natural products.