ETD system

Electronic theses and dissertations repository


Tesi etd-12212018-104740

Thesis type
Tesi di laurea magistrale LM5
Synthesis and optimization of benzoylpiperidine derivatives as Monoacylglycerol Lipase (MAGL) inhibitors.
Corso di studi
relatore Prof. Minutolo, Filippo
correlatore Dott.ssa Granchi, Carlotta
Parole chiave
  • Monoacylglycerol Lipase (MAGL)
Data inizio appello
Secretata d'ufficio
Data di rilascio
Riassunto analitico
Monoacylglycerol lipase (MAGL) is nowadays acknowledged as the main enzyme responsible for the deactivation of the most abundant brain endocannabinoid, 2-arachidonoylglycerol (2-AG).
It is an intracellular cytosolic serine hydrolase, expressed in the liver, in the adipose tissue and, most importantly, it is predominantly expressed in the brain. MAGL is involved in the hydrolysis of the 2-AG ester group, releasing glycerol and arachidonic acid. The pharmacological inhibition of this enzyme leads to the accumulation of 2-AG in the brain, and considering that 2-AG binds to cannabinoid receptors CB1 and CB2, the final outcome is expressed as an indirect cannabinergic effect. Therefore, MAGL is currently being considered as a promising drug target for a number of disorders whose treatment would benefit from this type of effect, including cancer, neurodegenerative and inflammatory diseases.
MAGL has progressively acquired a growing importance as a linker between the endocannabinoid system and eicosanoids system: in fact, by hydrolizing 2-AG, MAGL controls the release of arachidonic acid, which is the precursor of pro-inflammatory eicosanoids. Therefore, MAGL inhibition leads to analgesic and anti-inflammatory effects.
Furthermore, MAGL is upregulated in cancer cells and primary tumors and its inhibition in aggressive breast, ovarian, and melanoma cancer cells impairs cell migration, invasiveness, and tumorigenicity. All these functions have only started to be elucidated over the past few years thanks to the acquired knowledge on the structure of MAGL.
Many MAGL inhibitors are reported in the literature, although most of them showed an irreversible mechanism of action, which causes important side effects. Therefore, a great interest is directed to the discovery of reversible MAGL inhibitors. The application of computational studies in our department has recently led to the identification of compound GB18, that showed a reversible mechanism of MAGL inhibition, as suggested by modeling studies. So, starting from aforementioned lead compound, GB18 was modified to improve its activity in order to obtain the final compounds synthesized during my thesis work.

The aim of my thesis is the synthesis of new reversible MAGL inhibitors maintaining the benzoylpiperidine scaffold of GB18, in order to improve the MAGL inhibition activity. In particular, I introduced the following modifications:
the isopropyl group in the para position of the benzoyl part of compound GB18 was replaced with different groups;
the amidic phenyl ring of compound GB18 was replaced by pyridine rings;
the meta-hydroxy-substituted amidic fragment of compound GB18 was modified by introducing new substituents in the appropriate positions.
All the MAGL inhibitors synthetized during my thesis work were subjected to enzymatic inhibition
assays in human MAGL to measure their IC50 values.