RESUMEN
Attempts to optimize pharmacokinetic properties in a promising series of pyrrolopyrimidinone MARK inhibitors for the treatment of Alzheimer's disease are described. A focus on physical properties and ligand efficiency while prosecuting this series afforded key tool compounds that revealed a large discrepancy in the rat in vitro-in vivo DMPK (Drug Metabolism/Pharmacokinetics) correlation. These differences prompted an in vivo rat disposition study employing a radiolabeled representative of the series, and the results from this experiment justified the termination of any further optimization efforts.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinonas/farmacología , Pirroles/farmacología , Enfermedad de Alzheimer/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Pirimidinonas/química , Pirimidinonas/metabolismo , Pirroles/química , Pirroles/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
The initial structure activity relationships around an isoindoline uHTS hit will be described. Information gleaned from ligand co-crystal structures allowed for rapid refinements in both MARK potency and kinase selectivity. These efforts allowed for the identification of a compound with properties suitable for use as an in vitro tool compound for validation studies on MARK as a viable target for Alzheimer's disease.
Asunto(s)
Diseño de Fármacos , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinonas/farmacología , Pirroles/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Línea Celular , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Pirimidinonas/síntesis química , Pirimidinonas/química , Pirroles/síntesis química , Pirroles/química , Relación Estructura-ActividadRESUMEN
[reaction: see text] A synthesis of a pectenotoxin 4 C1-C15 segment is reported. Suitable C1-C7 and C8-C15 segments were prepared, coupled, converted to I and the C3-hydroxy variant, and then cyclized. Key findings include the stereoselective conversion of the allene to the corresponding spirodiepoxide, oxidative cleavage of the p-methoxybenzyl ether, and cyclization of the spirodiepoxide to spiroketal II.