- Identification of ABX-1431, a Selective Inhibitor of Monoacylglycerol Lipase and Clinical Candidate for Treatment of Neurological Disorders
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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 suppresses pain behavior in the rat formalin pain model. ABX-1431 (28) is currently under evaluation in human clinical trials.
- Cisar, Justin S.,Weber, Olivia D.,Clapper, Jason R.,Blankman, Jacqueline L.,Henry, Cassandra L.,Simon, Gabriel M.,Alexander, Jessica P.,Jones, Todd K.,Ezekowitz, R. Alan B.,O'Neill, Gary P.,Grice, Cheryl A.
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p. 9062 - 9084
(2018/09/06)
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- PYRROLO-PYRROLE CARBAMATE AND RELATED ORGANIC COMPOUNDS, PHARMACEUTICAL COMPOSITIONS, AND MEDICAL USES THEREOF
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The invention provides pyrrolo-pyrrole carbamate and related organic compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat medical disorders, e.g., solid tumor cancer, obesity, Down's syndrome, Alzheimer's disease, or pain, in a patient. The octahydropyrrolo pyrrole carbamates could be derived from hexafluoroisopropanol, Ν,Ν-disuccinimide and such. The activity of carbamates in MAGL, FAAH, and ABHD6 assays are also described.
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Paragraph 00360; 00361; 00367; 00368
(2015/01/16)
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