RESUMO
Previously, chemistry effort on the gem-cyclohexane series of gamma-secretase inhibitors has focused on the 4-position of the cyclohexane ring. Recently chemistry has been directed towards the 3-position and substitution here has also provided compounds with high gamma-secretase activity.
Assuntos
Doença de Alzheimer/patologia , Cicloexanos/química , Endopeptidases/metabolismo , Inibidores de Proteases/química , Sulfonas/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Cicloexanos/farmacologia , Humanos , Concentração Inibidora 50 , Modelos Químicos , Inibidores de Proteases/farmacologia , Estereoisomerismo , Sulfonas/farmacologiaRESUMO
The identification of a novel series of 7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines as GABA(A)alpha5 inverse agonists, which have both binding and functional (efficacy) selectivity for the benzodiazepine binding site of alpha5- over alpha1-, alpha2-, and alpha3-containing GABA(A) receptor subtypes, is described. Binding selectivity was determined to a large part by the degree of planarity of the fused ring system whereas functional selectivity was dependent on the nature of the heterocycle at the 3-position of the triazolopyridazine ring. 3-Furan and 5-methylisoxazole were shown to be optimal for GABA(A)alpha5 functional selectvity. 3-(5-Methylisoxazol-3-yl)-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine (43) was identified as a full inverse agonist at the GABA(A)alpha5 subtype with functional selectivity over the other GABA(A) receptor subtypes and good oral bioavailability.
Assuntos
Agonistas de Receptores de GABA-A , Isoxazóis/síntese química , Ftalazinas/síntese química , Triazóis/síntese química , Administração Oral , Animais , Sítios de Ligação , Disponibilidade Biológica , Linhagem Celular , Feminino , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Técnicas de Patch-Clamp , Ftalazinas/química , Ftalazinas/farmacocinética , Ftalazinas/farmacologia , Subunidades Proteicas/agonistas , Ensaio Radioligante , Ratos , Relação Estrutura-Atividade , Triazóis/farmacocinética , Triazóis/farmacologia , Xenopus laevisRESUMO
Nonselective inverse agonists at the gamma-aminobutyric acid(A) (GABA-A) benzodiazepine binding site have cognition-enhancing effects in animals but are anxiogenic and can precipitate convulsions. Herein, we describe novel GABA-A alpha5 subtype inverse agonists leading to the identification of 16 as an orally active, functionally selective compound that enhances cognition in animals without anxiogenic or convulsant effects. Compounds of this type may be useful in the symptomatic treatment of memory impairment associated with Alzheimer's disease and related dementias.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Agonistas de Receptores de GABA-A , Nootrópicos/síntese química , Ftalazinas/síntese química , Triazóis/síntese química , Animais , Ligação Competitiva , Disponibilidade Biológica , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Convulsivantes/síntese química , Convulsivantes/química , Convulsivantes/farmacologia , Cães , Humanos , Macaca mulatta , Camundongos , Nootrópicos/química , Nootrópicos/farmacologia , Oócitos/metabolismo , Técnicas de Patch-Clamp , Ftalazinas/química , Ftalazinas/farmacologia , Ensaio Radioligante , Ratos , Receptores de GABA-A/fisiologia , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologia , Xenopus laevisRESUMO
A new synthetic approach to tricyclic pyridones bearing a fused seven-membered ring is described. These compounds exhibit atropisomerism and exist in enantiomeric forms. Chiral HPLC separation of the enantiomers has allowed the rates of racemization to be measured and hence the free energy barrier for flipping the seven-membered ring to be deduced. Introduction of a further element of planar chirality leads to diastereomeric atropisomerism. The rate of interconversion of the diastereomers has been quantified by 2D EXSY NMR spectroscopy allowing a full description of the conformational dynamics of the system.
