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1.
J Med Chem ; 61(15): 6647-6657, 2018 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-30004704

RESUMEN

IDH1 plays a critical role in a number of metabolic processes and serves as a key source of cytosolic NADPH under conditions of cellular stress. However, few inhibitors of wild-type IDH1 have been reported. Here we present the discovery and biochemical characterization of two novel inhibitors of wild-type IDH1. In addition, we present the first ligand-bound crystallographic characterization of these novel small molecule IDH1 binding pockets. Importantly, the NADPH competitive α,ß-unsaturated enone 1 makes a unique covalent linkage through active site H315. As few small molecules have been shown to covalently react with histidine residues, these data support the potential utility of an underutilized strategy for reversible covalent small molecule design.


Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Histidina , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Isocitrato Deshidrogenasa/química , Línea Celular Tumoral , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Ligandos , Simulación del Acoplamiento Molecular , Mutación , Conformación Proteica , Relación Estructura-Actividad
2.
J Med Chem ; 50(13): 3086-100, 2007 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-17530838

RESUMEN

Stearoyl-CoA desaturase 1 (SCD1) catalyzes the committed step in the biosynthesis of monounsaturated fatty acids from saturated, long-chain fatty acids. Studies with SCD1 knockout mice have established that these animals are lean and protected from leptin deficiency-induced and diet-induced obesity, with greater whole body insulin sensitivity than wild-type animals. In this work, we have discovered a series of potent, selective, orally bioavailable SCD1 inhibitors based on a known pyridazine carboxamide template. The representative lead inhibitor 28c also demonstrates excellent cellular activity in blocking the conversion of saturated long-chain fatty acid-CoAs (LCFA-CoAs) to monounsaturated LCFA-CoAs in HepG2 cells.


Asunto(s)
Oxadiazoles/síntesis química , Piridazinas/síntesis química , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Acilcoenzima A/metabolismo , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Humanos , Técnicas In Vitro , Ratones , Microsomas Hepáticos/metabolismo , Oxadiazoles/farmacocinética , Oxadiazoles/farmacología , Piridazinas/farmacocinética , Piridazinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
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