RESUMO
BACKGROUND: Allosteric modulation of γ-secretase is an attractive therapeutic approach for the treatment of Alzheimer's disease. We recently identified a novel γ-secretase modulator, GSM-10h, which effectively lowers Aß42 production in cells and in amyloid precursor protein transgenic mice. OBJECTIVE: Here, we describe the in vivo characterization of GSM-10h in a model of endogenous Aß production. METHODS: Rats were administered orally with GSM-10h, and the effect on Aß levels in peripheral and central compartments was determined. In addition, the effect of GSM-10h on Notch processing was assessed. RESULTS: Acute administration of GSM-10h to rats causes a dose-dependent decrease in the level of Aß42 in plasma, CSF and brain, with little effect on the level of Aß40 in these compartments. The magnitude of Aß42 lowering in the CSF and brain was further enhanced upon sub-chronic administration of GSM-10h. No deleterious effect on Notch processing was evident in either of these studies. To further explore the dynamics of Aß42 reduction in peripheral and CNS compartments, a time course study was conducted. In all compartments, the decrease in Aß42 was greatest at 6 h after administration of GSM-10h. This decrease in Aß42 was maintained for 9-15 h, after which time Aß42 levels returned to baseline levels. Encouragingly, no rebound in Aß42 levels beyond baseline levels was observed. CONCLUSIONS: These findings support the γ-secretase modulator profile of GSM-10h, and highlight the utility of the rat for assessing the pre-clinical efficacy of γ-secretase modulators.
Assuntos
Acetatos/farmacologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Química Encefálica/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Fragmentos de Peptídeos/metabolismo , Piperidinas/farmacologia , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Contagem de Células , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/genética , Masculino , Neurônios/metabolismo , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/líquido cefalorraquidiano , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Receptores Notch/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Timo/citologia , Timo/efeitos dos fármacos , Fatores de Transcrição HES-1RESUMO
BACKGROUND: Cleavage of the amyloid precursor protein (APP) by ß-site APP-cleaving enzyme and γ-secretase results in the generation of amyloid-ß (Aß) peptides that aggregate and deposit as senile plaques in brains of Alzheimer disease patients. Due to the fundamental role γ-secretase plays in the proteolysis of a number of proteins including Notch, pharmacological inhibition of γ-secretase has been associated with mechanism-based toxicities. Therefore, efforts have focussed on the modulation of γ-secretase activity to selectively decrease levels of Aß42 peptide while avoiding deleterious activity on Notch processing. OBJECTIVE: Here, we describe the in vitro and in vivo characterisation of a novel γ-secretase modulator, GSM-10h, and investigate the potential for shorter Aß peptides to induce neurotoxicity in rat primary cortical neurons. METHODS: The effect of GSM-10h on Aß levels was investigated in SH-SY5Y cells expressing mutant APP and in TASTPM mice expressing APP and presenilin-1 mutant transgenes. The effect of GSM-10h on Notch processing was also determined. RESULTS: In cells, GSM-10h decreased levels of Aß42 while concomitantly increasing levels of Aß38 in the absence of effects on Aß40 levels. In TASTPM mice, GSM-10h effectively lowered brain Aß42 and increased brain Aß38, with no effect on Notch signalling. Unlike Aß42, which causes neuronal cell death, neither Aß37 nor Aß38 were neurotoxic. CONCLUSIONS: These findings confirm GSM-10h exhibits the profile of a γ-secretase modulator. In addition, TASTPM mice are shown to be responsive to treatment with a γ-secretase modulator, thereby highlighting the utility of this bitransgenic mouse model in drug discovery efforts focussed on the development of γ-secretase modulators.
Assuntos
Acetatos/farmacologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/genética , Peptídeos beta-Amiloides/antagonistas & inibidores , Precursor de Proteína beta-Amiloide/biossíntese , Fragmentos de Peptídeos/antagonistas & inibidores , Piperidinas/farmacologia , Presenilina-1/biossíntese , Precursor de Proteína beta-Amiloide/genética , Animais , Morte Celular/efeitos dos fármacos , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Presenilina-1/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Transgenes/genéticaRESUMO
Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios.
