Optimization of 1,2,5‐Thiadiazole Carbamates as Potent and Selective ABHD6 Inhibitors

At present, inhibitors of α/β‐hydrolase domain 6 (ABHD6) are viewed as a promising approach to treat inflammation and metabolic disorders. This article describes the development of 1,2,5‐thiadiazole carbamates as ABHD6 inhibitors. Altogether, 34 compounds were synthesized, and their inhibitory activity was tested using lysates of HEK293 cells transiently expressing human ABHD6 (hABHD6). Among the compound series, 4‐morpholino‐1,2,5‐thiadiazol‐3‐yl cyclooctyl(methyl)carbamate (JZP‐430) potently and irreversibly inhibited hABHD6 (IC50=44 nM) and showed ∼230‐fold selectivity over fatty acid amide hydrolase (FAAH) and lysosomal acid lipase (LAL), the main off‐targets of related compounds. Additionally, activity‐based protein profiling indicated that JZP‐430 displays good selectivity among the serine hydrolases of the mouse brain membrane proteome. JZP‐430 has been identified as a highly selective, irreversible inhibitor of hABHD6, which may provide a novel approach in the treatment of obesity and type II diabetes.

[1]  R. McGuire,et al.  Discovery of glycine sulfonamides as dual inhibitors of sn-1-diacylglycerol lipase α and α/β-hydrolase domain 6. , 2014, Journal of medicinal chemistry.

[2]  Eric A. Horne,et al.  ABHD6 Blockade Exerts Antiepileptic Activity in PTZ-Induced Seizures and in Spontaneous Seizures in R6/2 Mice , 2014, Neuron.

[3]  John T. Melchior,et al.  The serine hydrolase ABHD6 Is a critical regulator of the metabolic syndrome. , 2013, Cell reports.

[4]  Landon R. Whitby,et al.  Discovery and optimization of piperidyl-1,2,3-triazole ureas as potent, selective, and in vivo-active inhibitors of α/β-hydrolase domain containing 6 (ABHD6). , 2013, Journal of medicinal chemistry.

[5]  J. Leppänen,et al.  Chiral 1,3,4-oxadiazol-2-ones as highly selective FAAH inhibitors. , 2013, Journal of medicinal chemistry.

[6]  Patrice D Cani,et al.  Implication of the anti-inflammatory bioactive lipid prostaglandin D2-glycerol ester in the control of macrophage activation and inflammation by ABHD6 , 2013, Proceedings of the National Academy of Sciences.

[7]  L. Parsons,et al.  Evaluation of NHS carbamates as a potent and selective class of endocannabinoid hydrolase inhibitors. , 2013, ACS chemical neuroscience.

[8]  J. Poupaert,et al.  Insight into the medicinal chemistry of the endocannabinoid hydrolase inhibitors. , 2013, Current medicinal chemistry.

[9]  F. Tchantchou,et al.  Selective inhibition of alpha/beta-hydrolase domain 6 attenuates neurodegeneration, alleviates blood brain barrier breakdown, and improves functional recovery in a mouse model of traumatic brain injury. , 2013, Journal of neurotrauma.

[10]  B. Cravatt,et al.  Chemical Probes of Endocannabinoid Metabolism , 2013, Pharmacological Reviews.

[11]  A. Poso,et al.  Piperazine and piperidine triazole ureas as ultrapotent and highly selective inhibitors of monoacylglycerol lipase. , 2013, Chemistry & biology.

[12]  Anna L. Bowman,et al.  Highly Predictive Ligand‐based Pharmacophore and Homology Models of ABHD6 , 2013, Chemical biology & drug design.

[13]  J. Laitinen,et al.  Biochemical and pharmacological characterization of human α/β-hydrolase domain containing 6 (ABHD6) and 12 (ABHD12)[S] , 2012, Journal of Lipid Research.

[14]  B. Cravatt,et al.  DAGLβ Inhibition Perturbs a Lipid Network Involved in Macrophage Inflammatory Responses , 2012, Nature chemical biology.

[15]  L. Parsons,et al.  Highly selective inhibitors of monoacylglycerol lipase bearing a reactive group that is bioisosteric with endocannabinoid substrates. , 2012, Chemistry & biology.

[16]  G. Muccioli,et al.  Inhibitors of the endocannabinoid-degrading enzymes, or how to increase endocannabinoid's activity by preventing their hydrolysis. , 2012, Recent patents on CNS drug discovery.

[17]  J. Laitinen,et al.  The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors , 2012, Acta physiologica.

[18]  Eric A. Horne,et al.  Dual Inhibition of α/β-Hydrolase Domain 6 and Fatty Acid Amide Hydrolase Increases Endocannabinoid Levels in Neurons* , 2011, The Journal of Biological Chemistry.

[19]  W. Hunter,et al.  Exploiting the high-resolution crystal structure of Staphylococcus aureus MenH to gain insight into enzyme activity , 2011, BMC Structural Biology.

[20]  M. Lindstrom,et al.  Identification of potent, noncovalent fatty acid amide hydrolase (FAAH) inhibitors. , 2011, Bioorganic & medicinal chemistry letters.

[21]  M. Pangalos,et al.  Monoacylglycerol Lipase Activity Is a Critical Modulator of the Tone and Integrity of the Endocannabinoid System , 2010, Molecular Pharmacology.

[22]  B. Cravatt,et al.  Endocannabinoid Overload , 2010, Molecular Pharmacology.

[23]  Sherry L. Niessen,et al.  Superfamily-wide portrait of serine hydrolase inhibition achieved by library-versus-library screening , 2010, Proceedings of the National Academy of Sciences.

[24]  N. Drouot,et al.  Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism. , 2010, American journal of human genetics.

[25]  Peter T. Nguyen,et al.  Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system , 2010, Nature Neuroscience.

[26]  Agnes L. Bodor,et al.  The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors , 2010, Nature Neuroscience.

[27]  O. Wiest,et al.  Thiadiazole carbamates: potent inhibitors of lysosomal acid lipase and potential Niemann-Pick type C disease therapeutics. , 2010, Journal of medicinal chemistry.

[28]  T. Nevalainen,et al.  Discovery and development of endocannabinoid-hydrolyzing enzyme inhibitors. , 2010, Current topics in medicinal chemistry.

[29]  J. Laitinen,et al.  Characterization of binding properties of monoglyceride lipase inhibitors by a versatile fluorescence-based technique. , 2010, Analytical biochemistry.

[30]  J. Long,et al.  Characterization of tunable piperidine and piperazine carbamates as inhibitors of endocannabinoid hydrolases. , 2010, Journal of medicinal chemistry.

[31]  B. Cravatt,et al.  A Comprehensive Profile of Brain Enzymes that Hydrolyze the Endocannabinoid 2‐Arachidonoylglycerol , 2007, Chemistry & biology.

[32]  B. Cravatt,et al.  A functional proteomic strategy to discover inhibitors for uncharacterized hydrolases. , 2007, Journal of the American Chemical Society.

[33]  Antti Poso,et al.  Fatty acid amide hydrolase inhibitors from virtual screening of the endocannabinoid system. , 2006, Journal of medicinal chemistry.

[34]  Giovanni Piersanti,et al.  Cyclohexylcarbamic acid 3'- or 4'-substituted biphenyl-3-yl esters as fatty acid amide hydrolase inhibitors: synthesis, quantitative structure-activity relationships, and molecular modeling studies. , 2004, Journal of medicinal chemistry.