RESUMO
Introduction of selected amine containing side chains into the 3-position of N',2-diphenylquinoline-4-carbohydrazide based NK3 antagonists abolishes unwanted hPXR activation. Introduction of a fluorine at the 8-position is necessary to minimize unwanted hI(Kr) affinity and a piperazine N-tert-butyl group is necessary for metabolic stability. The lead compound (8m) occupies receptors within the CNS following oral dosing (Occ(90) 7 mg/kg po; plasma Occ(90) 0.4 microM) and has good selectivity and excellent PK properties.
Assuntos
Flúor/química , Hidrazinas/química , Neurotransmissores/farmacologia , Piperazinas/química , Quinolinas/química , Receptores da Neurocinina-3/antagonistas & inibidores , Administração Oral , Animais , Células CHO , Cricetinae , Relação Dose-Resposta a Droga , Flúor/farmacologia , Hidrazinas/farmacologia , Piperazinas/farmacologia , Quinolinas/farmacologia , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A new class of potent NK3R antagonists based on the N',2-diphenylquinoline-4-carbohydrazide core is described. In an ex vivo assay in gerbil, the lead compound 2g occupies receptors within the CNS following oral dosing (Occ(90) 30 mg/kg po; plasma Occ(90) 0.95 microM) and has good selectivity and promising PK properties.
Assuntos
Hidrazinas/química , Hidrazinas/farmacologia , Neurotransmissores/química , Neurotransmissores/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Receptores da Neurocinina-3/antagonistas & inibidores , Administração Oral , Animais , Células CHO , Cricetinae , Relação Dose-Resposta a Droga , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
The identification of a series of imidazo[1,2-b][1,2,4]triazines with high affinity and functional selectivity for the GABA(A) alpha3-containing receptor subtype is described, leading to the identification of a clinical candidate, 11. Compound 11 shows good bioavailability and half-life in preclinical species, and it is a nonsedating anxiolytic in both rat and squirrel monkey behavioral models.
