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/químicaAsunto(s)
Benceno/química , Antagonistas de los Receptores Histamínicos/química , Oxazoles/química , Pirrolidinas/química , Receptores Histamínicos H3/química , Animales , Células CACO-2 , Línea Celular , Trastornos del Conocimiento/tratamiento farmacológico , Agonismo Inverso de Drogas , Humanos , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Oxazoles/farmacocinética , Pirrolidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptores Histamínicos H3/metabolismo , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacocinéticaRESUMEN
H(3)R inverse agonists based on an aminopropoxy-phenyloxazoline framework constitute highly valuable druglike lead compounds that display efficacy in a mouse model of recognition memory.
Asunto(s)
Antagonistas de los Receptores Histamínicos H3/farmacología , Oxazoles/farmacología , Receptores Histamínicos H3/química , Animales , Células CHO , Células CACO-2 , Línea Celular , Cricetinae , Cricetulus , Diseño de Fármacos , Agonismo Inverso de Drogas , Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/química , Humanos , Imidazoles/química , Ratones , Oxazoles/síntesis química , Oxazoles/química , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Wistar , Receptores Histamínicos H3/metabolismo , Relación Estructura-ActividadRESUMEN
SAR around 4,6-diaminopyrimidine derivatives allowed the discovery of the first potent dual M(3) antagonists and PDE4 inhibitors. Various chemical modulations around that scaffold led to the discovery of ucb-101333-3 which is characterized by the most interesting profile on both targets.