RESUMEN
The disclosed 3-phenyl-5-isothiazole carboxamides are potent allosteric antagonists of mGluR1 with generally good selectivity relative to the related group 1 receptor mGluR5. Pharmacokinetic properties of a member of this series (1R,2R)-N-(3-(4-methoxyphenyl)-4-methylisothiazol-5-yl)-2-methylcyclopropanecarboxamide (14) are good, showing acceptable plasma and brain exposure after oral dosing. Oral administration of isothiazole 14 gave robust activity in the formalin model of persistent pain which correlated with CNS receptor occupancy.
Asunto(s)
Amidas/síntesis química , Analgésicos/síntesis química , Antagonistas de Aminoácidos Excitadores/síntesis química , Dolor/tratamiento farmacológico , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Tiazoles/síntesis química , Administración Oral , Amidas/administración & dosificación , Amidas/farmacocinética , Analgésicos/administración & dosificación , Analgésicos/farmacocinética , Animales , Disponibilidad Biológica , Encéfalo/metabolismo , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Antagonistas de Aminoácidos Excitadores/farmacocinética , Humanos , Dolor/metabolismo , Dimensión del Dolor , Ratas , Ratas Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/administración & dosificación , Tiazoles/farmacocinéticaRESUMEN
The authors show by illustration that procedures used to validate the reliability of single-concentration high-throughput screens such as the signal window and Z' factor do not ensure sufficient reliability in potency estimates from concentration response assays. They develop the minimum significant ratio as a statistical parameter to characterize the fold change between 2 compounds run in the same experiment that can be considered a real difference and use this parameter to characterize the reliability of the assay. They adapt methods described by Bland and Altman to develop a simple set of 2 experiments to estimate the minimum significant ratio and show that this protocol can identify assays that lack reproducibility. The methods are then extended to validate the equivalency of the same assay run by multiple laboratories.
