RESUMEN
The discovery of a novel series of therapeutic agents that has been designed and optimized for treating chronic obstructive pulmonary disease is reported. The pharmacological strategy was based on the identification of compounds that inhibit a defined subset of kinase enzymes modulating inflammatory processes that would be effective against steroid refractory disease and exhibit a sustained duration of action after inhaled delivery.
Asunto(s)
Asma/tratamiento farmacológico , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Animales , Asma/metabolismo , Relación Dosis-Respuesta a Droga , Resistencia a Medicamentos/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Esteroides/farmacología , Relación Estructura-Actividad , Células U937RESUMEN
Allosteric activators of the glucose-sensing enzyme glucokinase (GK) are currently attracting much interest as potential antidiabetic therapies because they can achieve powerful blood glucose lowering through actions in multiple organs. Here, the optimization of a weakly active high-throughput screening hit to (2 R)-2-(4-cyclopropanesulfonylphenyl)- N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide (PSN-GK1), a potent GK activator with an improved pharmacokinetic and safety profile, is described. Following oral administration, this compound elicited robust glucose lowering in rats.
Asunto(s)
Glucoquinasa/metabolismo , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Sulfonas/química , Sulfonas/farmacología , Tiazoles/química , Tiazoles/farmacología , Animales , Activación Enzimática , Femenino , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacocinética , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/enzimología , Ratas , Ratas Sprague-Dawley , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-Actividad , Sulfonas/efectos adversos , Sulfonas/farmacocinética , Tiazoles/efectos adversos , Tiazoles/farmacocinéticaRESUMEN
Palladium-catalysed reaction of unprotected 2-, 3-, and 4-iodophenols with a range of amino acid derived organozinc reagents (not used in excess) gives the expected products in good to excellent yield, demonstrating that carbon-zinc bonds are not protonated by acidic phenols under the conditions of palladium-catalysed coupling reactions.
RESUMEN
Replacing the N-Boc-protecting group on a beta-amino organo-zinc reagent with a trifluoroacetyl group, which would be expected to make the nitrogen a better leaving group, results in a reagent that is more stable towards elimination.
