Masullo, Dario (2017) Identification of new synthetic and semi-synthetic derivatives for the treatment of entero-hepatic disorders. [Tesi di dottorato]

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Abstract

Bile acids, the end product of cholesterol metabolism, got researchers attention in the last twenty years for their ability to act as signal molecules. They are involved in multiple metabolic processes and, for this reason, they could be interesting lead compounds for the treatment of various diseases linked to metabolic syndrome. Due to their small chemical structure, bile acids are promiscuous molecules; indeed, they are able to bind both nuclear and G-protein coupled receptors, but, in some cases, in an unspecific manner. This promiscuity could lead to an unwanted activation of one of the two mentioned receptor class that could results in undesired side effects. For this reason, it became fundamental to understand the key pharmacophoric portions in that kind of molecules in order to know which part of them is responsible for the activation of one or both that receptors class. In this context, most of my Ph.D. was spent on the speculation on different bile acid scaffolds, where modifications were done in order understand the selectivity criteria behind the activation of one of the two receptors classes, improving their activity towards them. The modifications carried out generated a first class of novel selective and dual FXR, GPBAR1 (a G-protein coupled receptor) and LXR

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