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Tesi etd-02122020-145557


Thesis type
Tesi di laurea magistrale LM5
Author
COMPARINI, LUCREZIA MARGHERITA
URN
etd-02122020-145557
Title
New modifications of 1,3-diaza-4oxa-[3.3.1]bicyclic scaffolds as novel GLP-1 agonists
Struttura
FARMACIA
Corso di studi
CHIMICA E TECNOLOGIA FARMACEUTICHE
Supervisors
relatore Prof. Pineschi, Mauro
relatore Dott. Menichetti, Andrea
Parole chiave
  • diabetes
  • GLP-1
  • bicyclic
Data inizio appello
04/03/2020;
Consultabilità
Parziale
Data di rilascio
04/03/2023
Riassunto analitico
Diabetes mellitus is a complex metabolic disorder whose main clinical and diagnostic feature is hyperglycaemia. Diabetes is among the most common and prominent diseases in various countries of the world and in particular Type-2 diabetes (T2DM) is prevalent in 90% of the population suffering from this pathology.
Recently an interesting new target for this disease has been identified as the glucagon-like peptide-1 receptor (GLP-1R) that belongs to secretin like (class B) family of G‐protein‐coupled receptors (GPCRs). Glucagon-like peptide-1 (GLP-1) is a tissue-specific post-translational proteolytic product of the proglucagon gene that is released from intestinal L-cells in response to nutrient ingestion and enhances glucose-stimulated insulin secretion from pancreatic -cells.
Some GLP-1 mimetics peptides not degraded by DPP-4 are now commercially available, but all of these show problems of stability and administration route. For this reason, there is a huge interest in novel treatments that have similar physiological effects to GLP-1, which can be administered orally and minimize side effects.
Recently, our research group synthesized a hit compound having oxadiaza-[3.3.1]-bicyclic nonene motif, that showed GLP-1 secretagogue activity in the low micromolar range. The synthesis of these types of compounds follows four linear synthetic steps starting from pyridine, from which 1,2-dihydropyridine can be formed by using common literature protocols. The crucial steps consist on nitroso Diels-Alder reactions (NDA) of 1,2- dihydropyridines with the appropriate in situ oxidized hydroxamic acid, followed by a [3,3]-sigmatropic rearrangement of the inverse cycloadducts that provides bicyclic dioxazines. The reductive elaboration of dioxazines with Super Hydride® afforded oxadiazabicyclo[3.3.1]-nonene scaffolds by a cascade reaction.
Hence, this thesis aimed to the extension of the library of compounds by diversification of building blocks, in order to gain more active compounds through a preliminary study of structure-properties relationship. In particular:
• we introduced different kinds of substituents using various types of organometallic reagents (in the first step of the synthetic pathway) and hydroxamic acids (in the second step of the synthetic pathway)
• we attempted further manipulations on the 1,3-diaza-4oxa-[3.3.1]bicycle at a late stage such as coupling reactions, carboxylation or reduction
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