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J Med Chem ; 59(11): 5356-67, 2016 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-27167608


Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.

1-Alquil-2-acetilglicerofosfocolina Esterasa/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Pirazoles/farmacología , Tiazoles/farmacología , 1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Sitios de Unión/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/química
Orthop Clin North Am ; 46(1): 1-8, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25435030


Postoperative pain control after total knee arthroplasty may be insufficient, resulting in insomnia, antalgic ambulation, and difficulty with rehabilitation. Current strategies, including the use of femoral nerve catheters, may control pain but have been associated with falls, motor blockade, and quadriceps inhibition. Periarticular infiltration using the appropriate technique and knowledge of intraarticular knee anatomy may increase pain control and maximize rehabilitation.

Analgésicos/administración & dosificación , Anestesia Local , Anestésicos/administración & dosificación , Artroplastia de Reemplazo de Rodilla/efectos adversos , Articulación de la Rodilla/anatomía & histología , Dolor Postoperatorio/prevención & control , Humanos , Inyecciones Intraarticulares , Dolor Postoperatorio/etiología
Trends Endocrinol Metab ; 22(7): 275-85, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21489811


Largely as a result of rising obesity rates, the incidence of type 2 diabetes is escalating rapidly. Type 2 diabetes results from multi-organ dysfunctional glucose metabolism. Recent publications have highlighted hypothalamic insulin- and adipokine-sensing as a major determinant of peripheral glucose and insulin responsiveness. The preponderance of evidence indicates that the brain is the master regulator of glucose homeostasis, and that hypothalamic insulin and leptin signaling in particular play a crucial role in the development of insulin resistance. This review discusses the neuronal crosstalk between the hypothalamus, autonomic nervous system, and tissues associated with the pathogenesis of type 2 diabetes, and how hypothalamic insulin and leptin signaling are integral to maintaining normal glucose homeostasis.

Sistema Nervioso Autónomo/fisiología , Glucosa/metabolismo , Homeostasis , Hipotálamo/fisiología , Insulina/metabolismo , Leptina/metabolismo , Animales , Sistema Nervioso Autónomo/fisiopatología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Humanos , Hipotálamo/fisiopatología , Neuronas/fisiología , Sistema Nervioso Parasimpático/fisiología , Sistema Nervioso Parasimpático/fisiopatología , Sistema Nervioso Simpático/fisiología , Sistema Nervioso Simpático/fisiopatología