Universiteit Leiden

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Proefschrift

Discovery of Reversible Monoacylglycerol Lipase Inhibitors

Monoacylglycerol lipase (MAGL) is the principal enzyme responsible for hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL inhibition provides several potential therapeutic opportunities, including anti-nociceptive, anti-inflammatory and anti-cancer activity.

Auteur
Jiang, M.
Datum
17 maart 2022
Links
Thesis in Leiden Repository

Monoacylglycerol lipase (MAGL) is the principal enzyme responsible for hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL inhibition provides several potential therapeutic opportunities, including anti-nociceptive, anti-inflammatory and anti-cancer activity. This thesis describes the discovery of LEI-515 as peripherally restricted, reversible MAGL inhibitor. A library of 233.820 compounds was screened at the Pivot Park Screening Center and 7 hits were confirmed. Over 100 analogues of the most promising hit were designed, synthesized and evaluated in a natural substrate assay and activity-based protein profiling. This resulted in the identification of LEI-515, which has subnanomolar inhibitory potency, high selectivity and good metabolic stability. LEI-515 is a reversible inhibitor that forms a hemiketal with catalytic Ser122, stabilized by hydrogen bonds with Ala53 and Met123. LEI-515 is > 100-fold selective over a panel of 44 ion channels, receptors and enzymes, including the cannabinoid CB1 and CB2 receptor, hERG and cyclooxygenases. Targeted lipidomics revealed that LEI-515 increased cellular 2-AG levels in a concentration and time-dependent manner. Pharmacokinetic studies indicated that LEI-515 has excellent oral bioavailability, but does not penetrate the brain.

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