Cisar JS

References (3)

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.
ESTHER : Cisar_2018_J.Med.Chem_61_9062
PubMedSearch : Cisar_2018_J.Med.Chem_61_9062
PubMedID: 30067909

Title : Monoacylglycerol Lipase Inhibition in Human and Rodent Systems Supports Clinical Evaluation of Endocannabinoid Modulators - Clapper_2018_J.Pharmacol.Exp.Ther_367_494
Author(s) : Clapper JR , Henry CL , Niphakis MJ , Knize AM , Coppola AR , Simon GM , Ngo N , Herbst RA , Herbst DM , Reed AW , Cisar JS , Weber OD , Viader A , Alexander JP , Cunningham ML , Jones TK , Fraser IP , Grice CA , Ezekowitz RAB , O'Neill GP , Blankman JL
Ref : Journal of Pharmacology & Experimental Therapeutics , 367 :494 , 2018
Abstract : Monoacylglycerol lipase (MGLL) is the primary degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). The first MGLL inhibitors have recently entered clinical development for the treatment of neurologic disorders. To support this clinical path, we report the pharmacological characterization of the highly potent and selective MGLL inhibitor ABD-1970 [1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-chlorobenzyl)piperazine-1-carboxylate]. We used ABD-1970 to confirm the role of MGLL in human systems and to define the relationship between MGLL target engagement, brain 2-AG concentrations, and efficacy. Because MGLL contributes to arachidonic acid metabolism in a subset of rodent tissues, we further used ABD-1970 to evaluate whether selective MGLL inhibition would affect prostanoid production in several human assays known to be sensitive to cyclooxygenase inhibitors. ABD-1970 robustly elevated brain 2-AG content and displayed antinociceptive and antipruritic activity in a battery of rodent models (ED(50) values of 1-2 mg/kg). The antinociceptive effects of ABD-1970 were potentiated when combined with analgesic standards of care and occurred without overt cannabimimetic effects. ABD-1970 also blocked 2-AG hydrolysis in human brain tissue and elevated 2-AG content in human blood without affecting stimulated prostanoid production. These findings support the clinical development of MGLL inhibitors as a differentiated mechanism to treat pain and other neurologic disorders.
ESTHER : Clapper_2018_J.Pharmacol.Exp.Ther_367_494
PubMedSearch : Clapper_2018_J.Pharmacol.Exp.Ther_367_494
PubMedID: 30305428

Title : Metabolomics annotates ABHD3 as a physiologic regulator of medium-chain phospholipids - Long_2011_Nat.Chem.Biol_7_763
Author(s) : Long JZ , Cisar JS , Milliken D , Niessen S , Wang C , Trauger SA , Siuzdak G , Cravatt BF
Ref : Nat Chemical Biology , 7 :763 , 2011
Abstract : All organisms, including humans, possess a huge number of uncharacterized enzymes. Here we describe a general cell-based screen for enzyme substrate discovery by untargeted metabolomics and its application to identify the protein alpha/beta-hydrolase domain-containing 3 (ABHD3) as a lipase that selectively cleaves medium-chain and oxidatively truncated phospholipids. Abhd3(-/-) mice possess elevated myristoyl (C14)-phospholipids, including the bioactive lipid C14-lysophosphatidylcholine, confirming the physiological relevance of our substrate assignments.
ESTHER : Long_2011_Nat.Chem.Biol_7_763
PubMedSearch : Long_2011_Nat.Chem.Biol_7_763
PubMedID: 21926997
Gene_locus related to this paper: human-ABHD3 , mouse-abhd3