Cisar_2018_J.Med.Chem_61_9062

Reference

Title : Identification of ABX-1431, a Selective Inhibitor of Monoacylglycerol Lipase and Clinical Candidate for Treatment of Neurological Disorders - Cisar_2018_J.Med.Chem_61_9062
Author(s) : Cisar JS , Weber OD , Clapper JR , Blankman JL , Henry CL , Simon GM , Alexander JP , Jones TK , Ezekowitz RAB , O'Neill GP , Grice CA
Ref : Journal of Medicinal Chemistry , 61 :9062 , 2018
Abstract :

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.

PubMedSearch : Cisar_2018_J.Med.Chem_61_9062
PubMedID: 30067909

Related information

Inhibitor ABX-1431

Citations formats

Cisar JS, Weber OD, Clapper JR, Blankman JL, Henry CL, Simon GM, Alexander JP, Jones TK, Ezekowitz RAB, O'Neill GP, Grice CA (2018)
Identification of ABX-1431, a Selective Inhibitor of Monoacylglycerol Lipase and Clinical Candidate for Treatment of Neurological Disorders
Journal of Medicinal Chemistry 61 :9062

Cisar JS, Weber OD, Clapper JR, Blankman JL, Henry CL, Simon GM, Alexander JP, Jones TK, Ezekowitz RAB, O'Neill GP, Grice CA (2018)
Journal of Medicinal Chemistry 61 :9062