RESUMEN
A series of bicyclic pyridones were identified as potent inhibitors of catechol O-methyltransferase (COMT). Substituted benzyl groups attached to the basic nitrogen of the core scaffold gave the most potent inhibitors within this series. Rat pharmacokinetic studies showed medium to high levels of clearance for this series, but with high free fraction due to remarkably low levels of protein and tissue binding. In rat biomarker studies, levels of unbound drug exposure are seen in the brain, which exceed their respective IC50s, leading to changes in the levels of dopamine metabolites in a manner consistent with COMT inhibition.
RESUMEN
The simpler, the better: H(3) histamine receptor (H(3)R) are of interest as therapeutic targets in cognitive and somnolence disorders. Here, lead optimization of H(3)R inverse agonists bearing a thiazolo[5,4-c]piperidine group gave rise to a clinical candidate with a much simpler unprecedented benzamide scaffold, displaying decreased hERG activity while maintaining high brain receptor occupancies.
Asunto(s)
Agonistas de los Receptores Histamínicos/química , Agonistas de los Receptores Histamínicos/farmacología , Piperidinas/química , Piperidinas/farmacología , Receptores Histamínicos H3/metabolismo , Animales , Benzamidas/química , Benzamidas/farmacocinética , Benzamidas/farmacología , Células CACO-2 , Agonistas de los Receptores Histamínicos/farmacocinética , Humanos , Masculino , Piperidinas/farmacocinética , Ratas , Ratas Wistar , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacocinética , Tiazoles/farmacología , Transactivadores/metabolismo , Regulador Transcripcional ERGAsunto(s)
Antidepresivos/farmacología , Cognición/efectos de los fármacos , Receptores Histamínicos H3/metabolismo , Tiazoles/farmacología , Animales , Antidepresivos/síntesis química , Antidepresivos/química , Diseño de Fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/químicaRESUMEN
The discovery and optimization of a novel class of potent CCR3 antagonists is described. Details of synthesis and SAR are given together with some ADME properties of selected compounds. An optimal balance between activities, physicochemical properties, and in vitro metabolic stability was reached by the proper choice of substituents.
Asunto(s)
Piperidinas/farmacología , Receptores de Quimiocina/antagonistas & inhibidores , Humanos , Piperidinas/síntesis química , Piperidinas/química , Receptores CCR3 , Relación Estructura-ActividadRESUMEN
The synthesis and structure-activity relationships against the C3a receptor of a series of substituted aminopiperidine derivatives are reported. DMPK properties and functional activities of selected compounds are described. The compounds obtained are the first non-arginine ligands of C3aR.