RESUMEN
Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the S(1)(') active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model.
Asunto(s)
Inhibidores de la Metaloproteinasa de la Matriz , Osteoartritis/tratamiento farmacológico , Ácidos Picolínicos/química , Inhibidores de Proteasas/química , Tetrazoles/química , Administración Oral , Animales , Sitios de Unión , Cartílago/efectos de los fármacos , Cartílago/metabolismo , Dominio Catalítico , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Metaloproteinasa 13 de la Matriz/metabolismo , Ácidos Picolínicos/síntesis química , Ácidos Picolínicos/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Ratas , Tetrazoles/síntesis química , Tetrazoles/farmacología , Zinc/químicaRESUMEN
The aim of two studies was to examine both between-subjects and within-subjects associations between daily amounts of physical activity and sleep in the home environment. Study 1 examined self-reported exercise durations and sleep diaries for 105 consecutive days in 31 college students who were normal sleepers. Between-subjects associations of mean exercise with mean sleep were assessed with Spearman rank-order correlations. Within-subjects correlations were determined across 105 days, and by comparing sleep on the 11 most active vs. the 11 least active days. Study 2 examined 71 physically active adults (n=38 ages 18-30 years, and n=33 ages 60-75 years), the majority of whom were normal sleepers. Over seven consecutive days, physical activity was assessed via actigraphy and a diary-derived estimate of energy expenditure, and sleep was assessed via actigraphy and sleep diaries. Between-subjects associations of mean physical activity with mean sleep were assessed with partial correlations, controlling for age. Within-subjects associations were assessed with ANCOVAs, with daily physical activity serving as the covariate, and by comparing sleep on the most active vs. the least active day. No significant within-subjects associations between physical activity and sleep were found in the main analyses of either study. Two small, but significant, between-subjects correlations between different physical activity measures and subjective sleep were found in Study 2. These results fail to support epidemiologic data on the value of exercise for sleep, but are consistent with experimental evidence showing only modest effects of exercise on sleep.