Synthesis and pharmacological evaluation of lactams as Fatty Acid Amide Hydrolase inhibitors
(2025)
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- Abstract
- This thesis explores the development of lactam inhibitors of the enzyme FAAH (Fatty Acid Amide Hydrolase) using an interdisciplinary approach that combines organic synthesis, pharmacology, and docking studies. The main objective of this thesis was to better understand the interactions between lactam compounds and FAAH in order to design more effective inhibitors. The first investigations focused on bicyclic compounds to lock the syn configuration and avoid the formation of anti products. However, pharmacological tests revealed that the bicyclic inhibitors were not as effective as expected, suggesting the influence of other factors. Docking studies confirmed a different interaction mode for the monolactam compounds. Another aspect of this project was to investigate the importance of the stereochemistry by inverting the configuration of one of the asymmetric carbon centres. Preliminary results suggested a low influence of asymmetric centres on the inhibition of FAAH Additionally, the thesis examined the influence of the lactam ring size on FAAH inhibition. While γ-lactams and δ-lactams were considered, their synthesis was not completed due to prioritisation issues. Finally, our studies led us to design a new β-lactam, which combines two parameters studied separately in the pharmacophore investigation. This compound showed the best in cellulo properties. A docking study was also conducted to understand its mode of interaction with FAAH.
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Citations
Morelle, A. (2025). Synthesis and pharmacological evaluation of lactams as Fatty Acid Amide Hydrolase inhibitors. https://hdl.handle.net/2078.5/247434