ArticleBiochemical pharmacology2012
Covalent inhibition of recombinant human carboxylesterase 1 and 2 and monoacylglycerol lipase by the carbamates JZL184 and URB597.
Article in Biochemical pharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 35 citations in OpenAlex.
- Mechanistic insights into human carboxylesterase 2 (CES2) inhibition by the CES1 prodrug substrate remdesivir.Drug metabolism and disposition: the biological fate of chemicals · 2025Article
- An in vitro evaluation of common botanical extracts on carboxylesterase 1 catalytic activity.Drug metabolism and disposition: the biological fate of chemicals · 2025Article
- Carboxylesterase 1-mediated endocannabinoid metabolism in skin: role in melanoma progression in BRafCancer & metabolism · 2025Article
- Identification and validation of fusidic acid and flufenamic acid as inhibitors of SARS-CoV-2 replication using DrugSolver CavitomiX.Scientific reports · 2023Article
- Carboxylesterase 1d Inactivation Augments Lung Inflammation in Mice.ACS pharmacology & translational science · 2022Article
- Systematic identification of biomarker-driven drug combinations to overcome resistance.Nature chemical biology · 2022Article
- Pig Liver Esterases Hydrolyze Endocannabinoids and Promote Inflammatory Response.Frontiers in immunology · 2021Article
- Effects of the monoacylglycerol lipase inhibitor JZL184 on chickens infected with avian pathogenicCanadian journal of veterinary research = Revue canadienne de recherche veterinaire · 2020Article
- Design and Potency of Dual Soluble Epoxide Hydrolase/Fatty Acid Amide Hydrolase Inhibitors.ACS omega · 2018Article
- Human carboxylesterases: a comprehensive review.Acta pharmaceutica Sinica. B · 2018Review
- Endocannabinoid hydrolases in avian HD11 macrophages identified by chemoproteomics: inactivation by small-molecule inhibitors and pathogen-induced downregulation of their activity.Molecular and cellular biochemistry · 2018Article
- Identification and optimization of soluble epoxide hydrolase inhibitors with dual potency towards fatty acid amide hydrolase.Bioorganic & medicinal chemistry letters · 2018Article
- Metabolically Labile Fumarate Esters Impart Kinetic Selectivity to Irreversible Inhibitors.Journal of the American Chemical Society · 2016Article
- Interaction of the serine hydrolase KIAA1363 with organophosphorus agents: Evaluation of potency and kinetics.Archives of biochemistry and biophysics · 2016Article
- Simplified assays of lipolysis enzymes for drug discovery and specificity assessment of known inhibitors.Journal of lipid research · 2016Article
- Blocking of fatty acid amide hydrolase activity with PF-04457845 in human brain: a positron emission tomography study with the novel radioligand [(11)C]CURB.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2015Article
- Effects of toxicologically relevant xenobiotics and the lipid-derived electrophile 4-hydroxynonenal on macrophage cholesterol efflux: silencing carboxylesterase 1 has paradoxical effects on cholesterol uptake and efflux.Chemical research in toxicology · 2014Article
- Identification of palmitoyl protein thioesterase 1 in human THP1 monocytes and macrophages and characterization of unique biochemical activities for this enzyme.Biochemistry · 2013Article
- Acetylcholinesterase inhibitors: pharmacology and toxicology.Current neuropharmacology · 2013Article
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5 authors at 3 institutions in 1 country.
Funding
Abstract
Carboxylesterase type 1 (CES1) and CES2 are serine hydrolases located in the liver and small intestine. CES1 and CES2 actively participate in the metabolism of several pharmaceuticals. Recently, carbamate compounds were developed to inhibit members of the serine hydrolase family via covalent modification of the active site serine. URB597 and JZL184 inhibit fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively; however, carboxylesterases in liver have been identified as a major off-target. We report the kinetic rate constants for inhibition of human recombinant CES1 and CES2 by URB597 and JZL184. Bimolecular rate constants (k(inact)/K(i)) for inhibition of CES1 by JZL184 and URB597 were similar [3.9 (±0.2) × 10(3) M(-1) s(-1) and 4.5 (±1.3) × 10(3) M(-1) s(-1), respectively]. However, k(inact)/K(i) for inhibition of CES2 by JZL184 and URB597 were significantly different [2.3 (±1.3) × 10(2) M(-1) s(-1) and 3.9 (±1.0) × 10(3) M(-1) s(-1), respectively]. Rates of inhibition of CES1 and CES2 by URB597 were similar; however, CES1 and MAGL were more potently inhibited by JZL184 than CES2. We also determined kinetic constants for spontaneous reactivation of CES1 carbamoylated by either JZL184 or URB597 and CES1 diethylphosphorylated by paraoxon. The reactivation rate was significantly slower (4.5×) for CES1 inhibited by JZL184 than CES1 inhibited by URB597. Half-life of reactivation for CES1 carbamoylated by JZL184 was 49 ± 15 h, which is faster than carboxylesterase turnover in HepG2 cells. Together, the results define the kinetics of inhibition for a class of drugs that target hydrolytic enzymes involved in drug and lipid metabolism.
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