Rapacciuolo, Pasquale (2022) Multitarget-directed drugs: design, synthesis and pharmacological evaluation of ligands targeting G protein-coupled and nuclear receptors. [Tesi di dottorato]

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Abstract

Given the rise in the number of people conducting a sedentary lifestyle along with unhealthy diets on a global scale, the increase of dysmetabolic conditions mostly involving the liver, the intestine and the cardiovascular system has been steady in the last decades. As for the liver, two emerging conditions are non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). These two terms stand for a range of pathological conditions determined by an excessive fat build-up in the liver, whenever said build-up cannot be traced back to any secondary cause such as alcohol abuse. Although several pharmaceutical approaches have been investigated, NASH remains devoid of any effective drug therapy. Another non-communicable pathological condition is intestinal bowel disease (IBD). This term also withholds two main chronic inflammatory intestinal conditions: Crohn’s disease and ulcerative colitis. Both diseases present complex pathogenesis, and the symptoms can heavily impact the life quality of the patients. Together with these two enterohepatic conditions, it is very well known that dysmetabolism comes with a series of comorbidities mostly involving the cardiovascular system. Over the whole PhD work, all these conditions were the starting point for the identification of several small molecules which could be potentially applied to therapeutical protocols. Many molecular targets are involved in these multifactorial diseases. Considering the complexity of the molecular network underlying these conditions, the possibility of designing multi-target-oriented drugs represents a valid and potent tool to address these diseases. Starting from the long-standing expertise of my research group on the G protein-coupled bile acid receptor 1 (GPBAR1) and its involvement in liver and intestinal homeostasis, the aim of this PhD project was combining the pivotal structural information for GPBAR1 agonism with those allowing the modulation of interesting new targets also involved in pro-inflammatory conditions, such as leukotrienes receptors (CysLTRs), retinoic acid receptor-related orphan receptor gamma t (RORγt) and angiotensin-converting enzyme 2 (ACE2). Many chemical moieties have been studied during the design of new multi-target small molecules, ranging from heterocyclic quinoline derivatives to several semi-synthetic steroid-like compounds. A large family of dual GPBAR1 agonist and CysLT1R antagonist compounds was identified with the lead compound showing great effects on different models of inflamed liver. The identification of GPBAR1 agonists/RORγt inverse agonists proved instead very successful on a murine colitis model representing a potential class for the treatment of IBD. Furthermore, the identification of an in-house library of selective GPBAR1 agonists as ACE2 activators also allowed us to further investigate the activation mechanism of ACE2 itself and the effects of its activation on the interaction with SARS-CoV-2 Spike protein. In the end, the advancement to Phase I clinical trial of a potent FXR/GPBAR1 agonist, BAR502, determined the need to study its metabolic profile in animals and humans. To this end, several metabolites were synthesised to be used as standards for the qualitative and quantitative-oriented analysis of the products of BAR502 metabolic transformations.

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