RESUMEN
Genetic evidence points to deposition of amyloid-ß (Aß) as a causal factor for Alzheimer's disease. Aß generation is initiated when ß-secretase (BACE1) cleaves the amyloid precursor protein. Starting with an oxazine lead 1, we describe the discovery of a thiazine-based BACE1 inhibitor 5 with robust Aß reduction in vivo at low concentrations, leading to a low projected human dose of 14 mg/day where 5 achieved sustained Aß reduction of 80% at trough level.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores de Proteasas/química , Tiazinas/química , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Citocromo P-450 CYP2C9/química , Citocromo P-450 CYP2C9/metabolismo , Perros , Evaluación Preclínica de Medicamentos , Femenino , Semivida , Haplorrinos , Corazón/efectos de los fármacos , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/farmacología , Ratas , Ratas Sprague-Dawley , Tiazinas/metabolismo , Tiazinas/farmacologíaRESUMEN
Functional electrical stimulation (FES) can improve the gait of stroke patients by stimulating the peroneal nerve in the swing phase of the affected leg, causing dorsiflexion of the foot that allows the toes to clear the ground. A sensor can trigger the electrical stimulation automatically during the stroke gait. We previously used a heel sensor system, which detects the contact pressure of the heel, in FES to correct foot drop gait. However, the heel sensor has disadvantages in cosmetics and durability. Therefore, we have replaced the heel sensor with an acceleration sensor that can detect the swing phase based on the acceleration speed of the affected leg, using a machine learning technique (Neural Network). We have used a signal for heel contact in a gait using the heel sensor before training with the Neural Network. The accuracy of the Neural Network detector was compared with a swing phase detector based on the heel sensor. The Neural Network detector was able to detect similarly the swing phase in the heel sensor. The largest difference in timing of the swing phase was less than 60 milliseconds in normal subjects and 80 milliseconds in stroke patients. We were able to correct foot drop gait using FES with an acceleration sensor and Neural Network detector. The present results indicate that an acceleration sensor positioned on the thigh, which is cosmetically preferable to systems in which the sensor is farther from the entry point of the electrodes, is useful for correction of stroke gait using FES.