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
A new class of high affinity hNK1R antagonists based on seven-membered ring cores has been identified. This series, with relatively simple, compact structures, includes compounds with high affinity, good selectivity, and promising in vivo properties.
Assuntos
Lactamas/química , Antagonistas dos Receptores de Neurocinina-1 , Linhagem Celular , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of 4,4-disubstituted cyclohexylamine NK(1) antagonists containing a lactam ring is described. The compounds are brain penetrant and activity is demonstrated in a ferret emesis model.
Assuntos
Antieméticos/síntese química , Antieméticos/farmacologia , Lactamas/química , Lactamas/farmacologia , Taquicininas/antagonistas & inibidores , Amidas/química , Animais , Antieméticos/química , Gerbillinae , Humanos , Concentração Inibidora 50 , Lactamas/síntese química , Metilação , Estrutura Molecular , Receptores da Neurocinina-1/metabolismo , Relação Estrutura-Atividade , Taquicininas/metabolismoRESUMO
Treatment of tertiary formamides with a silylated diazoester in the presence of a rhodium(II) catalyst leads to the formation of 3-amino-2-silyloxyacrylates in good yield. No olefination is observed if a nonsilylated diazo compound is employed. [reaction: see text]
RESUMO
A series of novel 4,4-disubstituted cyclohexylamine based NK(1) antagonists is described. The effect of changes to the C(1)-C(4) relative stereochemistry on the cyclohexane ring and replacements for the flexible linker are discussed, leading to the identification of compounds with high affinity and good in vivo duration of action.
Assuntos
Cicloexilaminas/síntese química , Cicloexilaminas/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Animais , Sítios de Ligação , Células CHO , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Cricetinae , Cicloexilaminas/farmacocinética , Gerbillinae , Concentração Inibidora 50 , Conformação Molecular , Ensaio Radioligante , Receptores da Neurocinina-1/química , Relação Estrutura-AtividadeRESUMO
A series of novel 4,4-disubstituted cyclohexylamines as NK(1) receptor antagonists is described: modifications to the amine moiety retain NK(1) receptor binding affinity whilst disrupting I(Kr) affinity.
