San Diego, Nov. 15, 2016
Monoacylglycerol lipase (MGLL) is the primary regulator of 2-arachidonoylglycerol (2-AG) an endogenous ligand of the cannabinoid (CB) receptors CB1 and CB2. Selective blockade of MGLL inhibits the hydrolytic degradation of 2-AG resulting in elevated 2-AG levels in the CNS and periphery, and CB1/2-dependent anti-nociceptive and anti-inflammatory effects. In the rodent brain and select peripheral tissues, MGLL inactivation also reduces levels of the catabolic product of 2-AG hydrolysis, arachidonic acid, a metabolic precursor to pro-inflammatory prostanoids. Here, we present a comprehensive in vivo characterization of a selective covalent inhibitor of MGLL, ABD-1970. ABD-1970 is orally active in rodents producing a rapid and potent inhibition of MGLL and elevation of 2-AG in the brain. In vivo blockade of 2-AG hydrolysis was also associated with reduced levels of arachidonic acid and prostanoids PGE2, PGD2 and PGF2α in the brain. Using activity-based protein profiling to comprehensively profile the in vivo selectivity of ABD-1970 against other serine hydrolases, α/β-hydrolase domain-containing 6 (ABHD6) and rodent-specific carboxylesterase 1c (CES1c) were the only off-targets identified, albeit at doses above those required for in vivo pharmacological activity at MGLL. In time course experiments, MGLL activity was inversely correlated with ABD-1970 concentrations in the blood and brain with recovery of MGLL activity observed as the compound was eliminated from the body. Furthermore, ABD-1970 was efficacious in the rat incisional model of acute post-operative pain, the rat formalin and complete Freund’s adjuvant models of inflammatory pain and the rat chronic constriction injury model of neuropathic pain. In the formalin model, ABD-1970 produced enhanced activity in combination with standard of care agents, pregabalin and morphine. Integrated analysis of compound exposure, brain target engagement, and 2-AG levels reveal a strong relationship between PK, central biomarkers and efficacy in models of pain. Importantly, acute administration of ABD-1970 lacked effects on total exploratory activity in an open field test. These results identify ABD-1970 as a highly potent and selective in vivo active inhibitor of MGLL and underscore the therapeutic potential of selective MGLL inhibitors for the treatment of acute and chronic pain.