RESUMEN
A series of (N-benzyl-N-phenylsulfonamido)alkyl amides were developed from classic and parallel synthesis strategies. Compounds with good in vitro and in vivo γ-secretase activity were identified and described.
Asunto(s)
Amidas/química , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores de Proteasas/química , Sulfonamidas/química , Amidas/síntesis química , Amidas/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Fragmentos de Péptidos/metabolismo , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/metabolismo , Unión Proteica , Relación Estructura-ActividadRESUMEN
The synthesis and gamma-secretase inhibition data for a series of carbamate-appended N-alkylsulfonamides are described. Carbamate 54 was found to significantly reduce brain Abeta in transgenic mice. 54 was also found to possess markedly improved brain levels in transgenic mice compared to previously disclosed 1 and 2.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Carbamatos/química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ratones , Ratones Transgénicos , Relación Estructura-ActividadRESUMEN
The synthesis and gamma-secretase inhibition data for a series of nitrogen-appended N-alkylsulfonamides (11-47) are described. Inhibition of brain Abeta in transgenic mice was demonstrated by two of these compounds (23 and 44).
Asunto(s)
Aminas/química , Aminas/farmacología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Alquilación , Aminas/síntesis química , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Azoles/síntesis química , Azoles/química , Azoles/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Encéfalo/metabolismo , Interacciones Hidrofóbicas e Hidrofílicas , Concentración 50 Inhibidora , Ratones , Ratones Transgénicos , Fragmentos de Péptidos/metabolismo , Inhibidores de Proteasas/síntesis química , Relación Estructura-Actividad , Sulfonamidas/síntesis químicaRESUMEN
A series of amino-caprolactam sulfonamides were developed from a screening hit. Compounds with good in vitro and in vivo gamma-secretase activity are reported.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Caprolactama/farmacología , Inhibidores Enzimáticos/farmacología , Caprolactama/química , Inhibidores Enzimáticos/químicaRESUMEN
A series of N-alkylbenzenesulfonamides were developed from a high throughput screening hit. Classic and parallel synthesis strategies were employed to produce compounds with good in vitro and in vivo gamma-secretase activity.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Sulfonamidas/química , Sulfonamidas/farmacología , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ratones , Ratones Transgénicos , Estructura Molecular , Unión ProteicaRESUMEN
We report on the design of benzodiazepinones as peptidomimetics at the carboxy terminus of hydroxyamides. Structure-activity relationships of diazepinones were investigated and orally active gamma-secretase inhibitors were synthesized. Active metabolites contributing to Abeta reduction were identified by analysis of plasma samples from Tg2576 mice. In particular, (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796) was identified with an acceptable pharmacodynamic and pharmacokinetic profile. Chronic dosing of BMS-433796 in Tg2576 mice suggested a narrow therapeutic window and Notch-mediated toxicity at higher doses.
Asunto(s)
Alanina/análogos & derivados , Enfermedad de Alzheimer/enzimología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Benzodiazepinonas/farmacología , Inhibidores Enzimáticos/farmacología , Alanina/farmacología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides , Animales , Ratones , Ratones Transgénicos , Modelos MolecularesRESUMEN
RATIONALE: Alzheimer's dementia (AD) patients have profound deficits in cognitive and social functions, mediated in part by a decline in cholinergic function. Acetylcholinesterase inhibitors (AChEI) are the most commonly prescribed treatment for the cognitive deficits in AD patients, but their therapeutic effects are small, and it is still not clear if they primarily affect attention, memory, or some other cognitive/behavioral functions. OBJECTIVES: The objective of the present experiments was to explore the effects of donepezil (Aricepttrade mark), an AChEI, on behavioral deficits related exclusively to cholinergic dysfunction. MATERIALS AND METHODS: The effects of donepezil were assessed in Sprague-Dawley rats with scopolamine-induced deficits in a battery of cognitive/behavioral tests. RESULTS: Scopolamine produced deficits in contextual and cued fear conditioning, the 5-choice serial reaction time test, delayed nonmatching to position, the radial arm maze, and the Morris water maze. Analyses of the pattern and size of the effects revealed that donepezil produced very large effects on scopolamine-induced deficits in psychomotor function (approximately 20-50% of the variance), moderate-sized effects on scopolamine-induced deficits in simple conditioning and attention (approximately 3-10% of the variance), but only small effects on scopolamine-induced deficits in higher cognitive functions of working memory and spatial mapping (approximately 1% of the variance). CONCLUSIONS: These results are consistent with the limited efficacy of donepezil on higher cognitive function in AD patients, and suggest that preclinical behavioral models could be used not only to determine if novel treatments have some therapeutic potential, but also to predict more precisely what the pattern and size of the effects might be.
Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Trastornos del Conocimiento/tratamiento farmacológico , Indanos/farmacología , Piperidinas/farmacología , Trastornos Psicomotores/tratamiento farmacológico , Animales , Atención/efectos de los fármacos , Trastornos del Conocimiento/inducido químicamente , Condicionamiento Psicológico/efectos de los fármacos , Donepezilo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Antagonistas Muscarínicos , Trastornos Psicomotores/inducido químicamente , Ratas , Ratas Sprague-Dawley , EscopolaminaRESUMEN
Recent findings suggest that Alzheimer's dementia may be mediated by soluble beta amyloid (Abeta) more than the deposits of aggregated, insoluble Abeta, and vulnerability to cognitive deficits after scopolamine challenge may help identify AD even in patients that are still pre-symptomatic. The objectives of the present experiments were to determine if vulnerability to cognitive deficits after scopolamine challenge is related to levels of soluble Abeta, and if levels of soluble Abeta are more closely related to cognitive deficits than levels of insoluble Abeta, even in aged, transgenic mice, after they have developed very high levels of insoluble Abeta. Aged F-344 rats and young mice over-expressing the Swedish mutation in the human amyloid precursor protein (APPsw; Tg2576+) had elevated levels of soluble Abeta, and were more vulnerable to scopolamine challenge in the Morris water maze (MWM), relative to young rats and Tg2576- mice; but, among individual animals, higher levels of soluble Abeta were not correlated with vulnerability to scopolamine. On the other hand, in aged Tg2576+ mice, cognitive deficits were related to levels of soluble Abeta, not insoluble Abeta, despite the fact that the levels of insoluble Abeta were thousands of times higher than the levels of soluble Abeta. The results of the present experiments suggest that vulnerability to cognitive deficits after scopolamine challenge is not related to elevated levels of soluble Abeta, but that high levels of soluble Abeta are more closely correlated with cognitive deficits than the amount insoluble Abeta, even after large amounts of aggregated, insoluble Abeta have been deposited.
Asunto(s)
Envejecimiento/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Aprendizaje por Laberinto/fisiología , Estimulación Acústica , Péptidos beta-Amiloides/química , Precursor de Proteína beta-Amiloide/genética , Análisis de Varianza , Animales , Condicionamiento Clásico/fisiología , Miedo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Transgénicos , Antagonistas Muscarínicos/farmacología , Polímeros/química , Ratas , Ratas Endogámicas F344 , Reflejo de Sobresalto/fisiología , Escopolamina/farmacología , SolubilidadRESUMEN
2,3-Benzodiazepin-1,4-diones were designed as peptidomimetics at the carboxy terminus of hydroxyamides. Inhibition of brain Abeta production was improved by one of the compounds containing constrained modification.
Asunto(s)
Encéfalo/efectos de los fármacos , Endopeptidasas/metabolismo , Inhibidores de Proteasas/farmacología , Enfermedad de Alzheimer/enzimología , Amidas/química , Secretasas de la Proteína Precursora del Amiloide , Animales , Ácido Aspártico Endopeptidasas , Benzodiazepinas/síntesis química , Benzodiazepinas/farmacología , Encéfalo/metabolismo , Línea Celular , Diseño de Fármacos , Concentración 50 Inhibidora , Cetonas/síntesis química , Cetonas/farmacología , Ratones , Conformación Molecular , Imitación Molecular , Inhibidores de Proteasas/síntesis química , Unión ProteicaRESUMEN
Antagonists of serotonin 6 (5-HT6) receptors have been reported to enhance cognition in animal models of learning, although this finding has not been universal. We have assessed the therapeutic potential of the specific 5-HT6 receptor antagonists 4-amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide (Ro 04-6790) and 5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide (SB-271046) in rodent models of cognitive function. Although mice express the 5-HT6 receptor and the function of this receptor has been investigated in mice, all reports of activity with 5-HT6 receptor antagonists have used rat models. In the present study, receptor binding revealed that the pharmacological properties of the mouse receptor are different from the rat and human receptor: Ro 04-6790 does not bind to the mouse 5-HT6 receptor, so all in vivo testing included in the present report was conducted in rats. We replicated previous reports that 5-HT6 receptor antagonists produce a stretching syndrome previously shown to be mediated through cholinergic mechanisms, but Ro 04-6790 and SB-271046 failed to attenuate scopolamine-induced deficits in a test of contextual fear conditioning. We also failed to replicate the significant effects reported previously in both an autoshaping task and in a version of the Morris water maze. The results of our experiments are not consistent with previous reports that suggested that 5-HT6 antagonists might have therapeutic potential for cognitive disorders.