Diseño, síntesis y evaluación biológica de nuevos compuestos duales antagonistas del receptor h3 de histamina y antagonistas de receptores de sulfonilurea, como potenciales agentes terapéuticos para tratamiento de obesidad y de diabetes mellitus 2

Resumen

DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NEW DUAL COMPOUNDS, HISTAMINE H3 RECEPTOR ANTAGONISTS AND SULFONYLUREA RECEPTORS ANTAGONISTS, AS POTENTIAL TERAPEUTICAL FOR THE TREATMENT OF OBESITY AND DIABETES MELLITUS TYPE 2 Javier Ceras Arrese, Faculty of Sciences, University of Navarra (Spain), 2008. Obesity is a spreading disease and is the most relevant metabolism disease worldwide. Recent data show that more than 1,600 million people are overweight, among them, 400 million are obese. The consequences of obesity are serious. The probabilities of undergo associated conditions like diabetes mellitus type 2 or cardiovascular diseases rise as overweight does. And the social and economic costs of obesity and related diseases are huge. Many neurotransmitters are involved in the regulation of food intake and energy balance. Among them, histamine is thought to play a key role in the energetic homeostasis through its H3 receptor, whose antagonism causes a reduction of food intake and, reportedly, weight loss. The low success of the actual treatment makes obesity an most appealing therapeutic targets. The purpose of this study is the synthesis and biological evaluation of new compounds with a dual activity: antiobesity (through the antagonism of the H3 receptor) and antidiabetes (by increasing insulin release from the beta cells in the pancreas). 60 new compounds have been synthesized and their affinity toward the H3 receptor have been evaluated. The synthesized structures (ureas and sulfonylureas) are novel and open a new and interesting approach in this field of research. In this study, synthetic routes have been optimized and the mechanisms of the reactions have been studied. I have also carried out the structural elucidation of all synthesized compounds, with classic techniques like IR spectroscopy or nuclear magnetic resonance (RMN) and, in some cases, also with advanced techniques of RMN like HMBC and HMQC.