RESUMEN
Herein we report the design and synthesis of a series of simple phenol amide ERRγ agonists based on a hydrazone lead molecule. Our structure activity relationship studies in this series revealed the phenol portion of the molecule to be required for activity. Attempts to replace the hydrazone with more suitable chemotypes led to a simple amide as a viable alternative. Differential hydrogen-deuterium exchange experiments were used to help understand the structural basis for binding to ERRγ and aid in the development of more potent ligands.
Asunto(s)
Benzamidas/farmacología , Estrógenos/farmacología , Fenoles/farmacología , Receptores de Estrógenos/metabolismo , Benzamidas/síntesis química , Benzamidas/química , Sitios de Unión , Estabilidad de Medicamentos , Estrógenos/síntesis química , Estrógenos/química , Células HEK293 , Semivida , Humanos , Hidrazonas/síntesis química , Hidrazonas/química , Hidrazonas/farmacología , Microsomas Hepáticos/metabolismo , Estructura Molecular , Fenoles/síntesis química , Fenoles/química , Receptores de Estrógenos/química , Relación Estructura-ActividadRESUMEN
A series of orexin receptor antagonists was synthesized based on a substituted piperidine scaffold. Through traditional medicinal chemistry structure-activity relationships (SAR), installation of various groups at the 3-6-positions of the piperidine led to modest enhancement in receptor selectivity. Compounds were profiled in vivo for plasma and brain levels in order to identify candidates suitable for efficacy in a model of drug addiction.