ArticleEuropean journal of medicinal chemistry2011
Biphenyl-3-yl alkylcarbamates as fatty acid amide hydrolase (FAAH) inhibitors: steric effects of N-alkyl chain on rat plasma and liver stability.
Article in European journal of medicinal chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
9 citing papers in PubMed, 21 citations in OpenAlex.
- Molecular Determinants of EphA2 and EphB2 Antagonism Enable the Design of Ligands with Improved Selectivity.Journal of chemical information and modeling · 2023Article
- Inhibition of Fatty Acid Amide Hydrolase (FAAH) Regulates NF-kb Pathways Reducing Bleomycin-Induced Chronic Lung Inflammation and Pulmonary Fibrosis.International journal of molecular sciences · 2023Article
- Fatty Acid Amide Hydrolase (FAAH) Inhibition Plays a Key Role in Counteracting Acute Lung Injury.International journal of molecular sciences · 2022Article
- ArylACS omega · 2021Article
- Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2015Article
- O-(triazolyl)methyl carbamates as a novel and potent class of fatty acid amide hydrolase (FAAH) inhibitors.ChemMedChem · 2015Article
- Amino Acid Derivatives as Palmitoylethanolamide Prodrugs: Synthesis, In Vitro Metabolism and In Vivo Plasma Profile in Rats.PloS one · 2015Article
- Synthesis and biological evaluation of liguzinediol mono- and dual ester prodrugs as promising inotropic agents.Molecules (Basel, Switzerland) · 2014Article
- Metabolism-directed structure optimization of benzimidazole-based Francisella tularensis enoyl-reductase (FabI) inhibitors.Xenobiotica; the fate of foreign compounds in biological systems · 2014Article
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
Secondary alkylcarbamic acid biphenyl-3-yl esters are a class of Fatty Acid Amide Hydrolase (FAAH) inhibitors, which include the reference compounds URB597 and URB694. Given the intrinsic reactivity of the carbamate group, the in vivo potency of these molecules in rats is strongly affected by their hydrolysis in plasma or hepatic metabolism. In the present study, in vitro chemical and metabolic stability assays (rat plasma and rat liver S(9) fraction) were used to investigate the structure-property relationships (SPRs) for a focused series of title compounds, where lipophilicity and steric hindrance of the carbamate N-substituent had been modulated. The resulting degradation rates indicate that a secondary or tertiary alkyl group at the carbamate nitrogen atom increases hydrolytic stability towards rat plasma esterases. The calculated solvent accessible surface area (SASA) of the carbamate fragment was employed to describe the differences observed in rate constants of hydrolysis in rat plasma (log k(plasma)), suggesting that stability in plasma increases if the substituent exerts a shielding effect on the carbamate carbonyl. Stability in rat liver S(9) fraction is increased when a tertiary carbon is bound to the carbamate nitrogen atom, while other steric effects showed complex relationships with degradation rates. The SPRs here described may be applied at the pharmacokinetic optimization of other classes of carbamate FAAH inhibitors.
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Registered trials
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