Identification of ABX-1431, a Selective Inhibitor of Monoacylglycerol Lipase and Clinical Candidate for Treatment of Neurological Disorders

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.