DEL hit becomes brain-penetrant reversible MAGL inhibitor MAGLi 432
- A bicyclopiperazine hit from a DNA-encoded library was optimized by structure-guided design into compound 1.5 (MAGLi 432), a reversible MAGL inhibitor.
- The compound combines high potency, selectivity over other serine hydrolases and CNS drug-like properties, with a favorable oral half-life in rats.
- It inhibited MAGL in human brain homogenate and worked in mouse neuroinflammation models; the campaign was steered by a translational "Five-Star Matrix" framework.
💡 Points
Reversibility is the part I'd want here, since irreversible MAGL agents ran into CB1 desensitization on chronic dosing. A non-covalent DEL chemotype that already shows target engagement in human brain tissue is a good template, and I'd steal the habit of testing in human tissue early rather than at the end.