RESUMO
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.
Assuntos
Benzamidas/farmacologia , Estrogênios/farmacologia , Fenóis/farmacologia , Receptores de Estrogênio/metabolismo , Benzamidas/síntese química , Benzamidas/química , Sítios de Ligação , Estabilidade de Medicamentos , Estrogênios/síntese química , Estrogênios/química , Células HEK293 , Meia-Vida , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Hidrazonas/farmacologia , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Fenóis/síntese química , Fenóis/química , Receptores de Estrogênio/química , Relação Estrutura-AtividadeRESUMO
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.