| Autor: |
Cisar JS; Abide Therapeutics , 10835 Road to the Cure, Suite 250 , San Diego , California 92121 , United States., Weber OD; Abide Therapeutics , 10835 Road to the Cure, Suite 250 , San Diego , California 92121 , United States., Clapper JR; Abide Therapeutics , 10835 Road to the Cure, Suite 250 , San Diego , California 92121 , United States., Blankman JL; Abide Therapeutics , 10835 Road to the Cure, Suite 250 , San Diego , California 92121 , United States., Henry CL; Abide Therapeutics , 10835 Road to the Cure, Suite 250 , San Diego , California 92121 , United States., Simon GM; Vividion Therapeutics , 3565 General Atomics Court, Suite 100 , San Diego , California 92121 , United States., Alexander JP; Abide Therapeutics , 10835 Road to the Cure, Suite 250 , San Diego , California 92121 , United States., Jones TK; Abide Therapeutics , 10835 Road to the Cure, Suite 250 , San Diego , California 92121 , United States., Ezekowitz RAB; Abide Therapeutics , 10835 Road to the Cure, Suite 250 , San Diego , California 92121 , United States., O'Neill GP; Abide Therapeutics , 10835 Road to the Cure, Suite 250 , San Diego , California 92121 , United States., Grice CA; Abide Therapeutics , 10835 Road to the Cure, Suite 250 , San Diego , California 92121 , United States. |
| Abstrakt: |
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 (ED 50 = 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. |
