Identification of ABX-1431, a Selective Inhibitor of Monoacylglycerol Lipase and Clinical Candidate for Treatment of Neurological Disorders
| Autor: | Gary P. O'Neill, Todd K. Jones, Olivia D. Weber, Cheryl A. Grice, Cassandra L. Henry, Justin S. Cisar, Jacqueline L. Blankman, Jessica P. Alexander, R. Alan B. Ezekowitz, Jason R. Clapper, Gabriel M. Simon |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Agonist Male Pyrrolidines medicine.drug_class Pain Pharmacology Anxiolytic Piperazines 03 medical and health sciences chemistry.chemical_compound Mice Dogs In vivo Drug Discovery medicine Animals Humans Tissue Distribution Molecular Targeted Therapy Receptor Piperazine Dose-Response Relationship Drug Serine hydrolase Cannabinoid Receptor Agonists Monoacylglycerol Lipases Rats Monoacylglycerol lipase 030104 developmental biology chemistry Molecular Medicine Arachidonic acid Nervous System Diseases |
| Zdroj: | Journal of medicinal chemistry. 61(20) |
| ISSN: | 1520-4804 |
| Popis: | The serine hydrolase monoacylglycerol lipase (MGLL) converts the endogenous cannabinoid receptor agonist 2-arachidonoylglycerol (2-AG) and other monoacylglycerols into fatty acids and glycerol. Genetic or pharmacological inactivation of MGLL leads to elevation in 2-AG in the central nervous system and corresponding reductions in arachidonic acid and eicosanoids, producing antinociceptive, anxiolytic, and antineuroinflammatory effects without inducing the full spectrum of psychoactive effects of direct cannabinoid receptor agonists. Here, we report the optimization of hexafluoroisopropyl carbamate-based irreversible inhibitors of MGLL, culminating in a highly potent, selective, and orally available, CNS-penetrant MGLL inhibitor, 28 (ABX-1431). Activity-based protein profiling experiments verify the exquisite selectivity of 28 for MGLL versus other members of the serine hydrolase class. In vivo, 28 inhibits MGLL activity in rodent brain (ED50 = 0.5–1.4 mg/kg), increases brain 2-AG concentrations, and suppre... |
| Databáze: | OpenAIRE |
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