Discovery of selective diacylglycerol lipase β inhibitors

Zhu, N. (2024)

Doctoral Thesis

Diacylglycerol lipases (DAGLα and DAGLβ) are responsible for the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain and peripheral tissues. Selective DAGLβ inhibitors have been proposed as a potential treatment for inflammatory diseases with reduced potential for central nervous system (CNS) mediated side effects, but they are currently lacking. To develop DAGLβ selective inhibitors, a fluorescent biochemical assay was optimized and applied in a high-throughput screening (HTS) for DAGLβ. During the HTS, eight hits classified into four distinct chemotypes were identified. Subsequent structure-activity relationship (SAR) studies, focusing on hit 1 and its modifications, revealed a specific group as the modification hotspot crucial for achieving selectivity towards DAGLβ. Through an extensive SAR investigation, focusing on modifying this group, the first-in-class DAGLβ selective inhibitors, LEI-130 and LEI-131, were discovered. Following their discovery, LEI-130 and LEI-131 underwent comprehensive in vitro and in situ profiling studies. These investigations confirmed that LEI-130 and LEI-131 are selective and noncompetitive inhibitors of DAGLβ, effectively reducing inflammation.

• Endocannabinoid
• Diacylglycerol lipase β
• Inhibitors
• Noncompetitive

• All authors: Zhu, N.
• Supervisor: Stelt, M. van der
• Co-supervisor: Janssen, A.P.A.; Berg, R.J.B.H.N. van den
• Committee: Ubbink, M.; Artola Perez de Azanza, M.E.; Martin, N.I.; Geurink, P.P.; Esch, I.J.P. de
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden Institute of Chemistry (LIC), Faculty of Science, Leiden University
• Date: 2024-05-22