URB597

Table of Contents

Introduction

  • Potent, selective inhibitor of FAAH.
  • It has a high degree of membrane permeability, and its stable under various conditions (heat, acid, and simulated gastric fluid).
  • It doesn't interact with other components of the endocannabinoid system aside FAAH [1].
  • URB597 doesn't produce classical effects of cannabinoids, such as catalepsy, hypothermia and hyperphagia [1], neither has demostrated a significant toxicity at chronic doses.

Effects

Kathuria et. al (2002) [2]

  • It describes how URB597 was designed taking as starting point carbamic acid.
  • Former studies made use of \{alpha}-heterocycles

Fegley et. al (2005) [3]

  • In the brain: It diminishes significatively anandamide hydrolysis (it return to basal levels only after 24h) (ex vivo hydrolisis assay with deuterium-labeled anandamide).
  • In the brain: Increases anandamide/OEA/PEA (FAEs) levels significatively by at least 2h (ex vivo assay).
  • These effects of URB597 are dependent on the inhibition of FAAH, as it is shown by performing the same assays on -/-faah rats tissues (no effect).
  • Although significatively hydrolisis decrease of FAEs on the duodenum was observed, this wasn't translated on an increase of FAEs levels (this suggest a mechanism of degradation different from FAAH mediated hydrolisis in this tissue).
  • When administering anandamide, it is observed hypothermia, possibly mediated by CB1 activation in the hypothalamus. Accordingly, in vivo measures shows this effect on rats after conjunct URB597 administration.
  • However it doesn't increase the effects of OEA on hypophagia.
[1]
D. Piomelli et al., “Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597),” CNS drug reviews, vol. 12, no. 1, pp. 21–38, 2006, doi: 10.1111/j.1527-3458.2006.00021.x. Available: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1527-3458.2006.00021.x. [Accessed: Nov. 10, 2025]
[2]
S. Kathuria et al., “Modulation of anxiety through blockade of anandamide hydrolysis,” Nat med, vol. 9, no. 1, pp. 76–81, Jan. 2003, doi: 10.1038/nm803. Available: https://www.nature.com/articles/nm803. [Accessed: Nov. 13, 2025]
[3]
D. Fegley et al., “Characterization of the fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 3′-carbamoyl-biphenyl-3-yl ester (URB597): Effects on anandamide and oleoylethanolamide deactivation,” The journal of pharmacology and experimental therapeutics, vol. 313, no. 1, pp. 352–358, Apr. 2005, doi: 10.1124/jpet.104.078980. Available: https://www.sciencedirect.com/science/article/pii/S0022356524319238. [Accessed: Nov. 11, 2025]