Discovery of reversible monoacylglycerol lipase inhibitors

Jiang, M. (2022)

Doctoral Thesis

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.

• MAGL
• Reversible inhibitor,
• Highly selective
• Peripherally restricted

• All authors: Jiang, M.
• Supervisor: Stelt, M. van der; Boeckel, C.A.A. van
• Co-supervisor: Berg, R.J.B.H.N. van den
• Committee: Overkleeft, H.S.; Martin N.I.; Heitman, L.H.; Westen, G.J.P. van; Baggelaar, M.P.; Witkamp, R.F.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden Institute of Chemistry (LIC), Faculty of Science, Leiden University
• Date: 2022-03-17