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Synthesis and quantitative structure-activity relationship of fatty acid amide hydrolase inhibitors: Modulation at the N-portion of biphenyl-3-yl alkylcarbamates

  • Author(s): Mor, M
  • Lodola, A
  • Rivara, S
  • Vacondio, F
  • Duranti, A
  • Tontini, A
  • Sanchini, S
  • Piersanti, G
  • Clapper, JR
  • King, AR
  • Tarzia, G
  • Piomelli, D
  • et al.

Published Web Location

https://doi.org/10.1021/jm701631zCreative Commons Attribution 4.0 International Public License
Abstract

Alkylcarbamic acid biphenyl-3-yl esters are a class of fatty acid amide hydrolase (FAAH) inhibitors that comprises cyclohexylcarbamic acid 3′-carbamoylbiphenyl-3-yl ester (URB597), a compound with analgesic, anxiolytic-like and antidepressant-like properties in rat and mouse models. Here, we extended the structure-activity relationships (SARs) for this class of compounds by replacing the cyclohexyl ring of the parent compound cyclohexylcarbamic acid biphenyl-3-yl ester (URB524) (FAAH IC50 = 63 nM) with a selected set of substituents of different size, shape, flexibility, and lipophilicity. Docking experiments and linear interaction energy (LIE) calculations indicated that the N-terminal group of O-arylcarbamates fits within the lipophilic region of the substrate-binding site, mimicking the arachidonoyl chain of anandamide. Significant potency improvements were observed for the β-naphthylmethyl derivative 4q (IC50 = 5.3 nM) and its 3′-carbamoylbiphenyl-3-yl ester 4z (URB880, IC50 = 0.63 nM), indicating that shape complementarity and hydrogen bonds are crucial to obtain highly potent inhibitors. © 2008 American Chemical Society.

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