Novel propanamides as fatty acid amide hydrolase inhibitors

Alessandro Deplano, Carmine Marco Morgillo, Monica Demurtas, Emmelie Björklund, Mariateresa Cipriano, Mona Svensson, Sanaz Hashemian, Giovanni Smaldone, Emilia Pedone, F. Javier Luque, Maria G. Cabiddu, Ettore Novellino, Christopher J. Fowler, Bruno Catalanotti, Valentina Onnis

Research output: Contribution to journalArticle

Abstract

Fatty acid amide hydrolase (FAAH) has a key role in the control of the cannabinoid signaling, through the hydrolysis of the endocannabinoids anandamide and in some tissues 2-arachidonoylglycerol. FAAH inhibition represents a promising strategy to activate the cannabinoid system, since it does not result in the psychotropic and peripheral side effects characterizing the agonists of the cannabinoid receptors. Here we present the discovery of a novel class of profen derivatives, the N-(heteroaryl)-2-(4-((2-(trifluoromethyl)pyridin-4-yl)amino)phenyl)propanamides, as FAAH inhibitors. Enzymatic assays showed potencies toward FAAH ranging from nanomolar to micromolar range, and the most compounds lack activity toward the two isoforms of cyclooxygenase. Extensive structure-activity studies and the definition of the binding mode for the lead compound of the series are also presented. Kinetic assays in rat and mouse FAAH on selected compounds of the series demonstrated that slight modifications of the chemical structure could influence the binding mode and give rise to competitive (TPA1) or non-competitive (TPA14) inhibition modes.

Original languageEnglish
Pages (from-to)523-542
Number of pages20
JournalEuropean Journal of Medicinal Chemistry
Volume136
DOIs
Publication statusPublished - Jan 1 2017

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Keywords

  • Anandamide
  • Endocannabinoids
  • FAAH inhibitors
  • Fatty acid amide hydrolase
  • Heteroaryl propanamides

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Deplano, A., Morgillo, C. M., Demurtas, M., Björklund, E., Cipriano, M., Svensson, M., Hashemian, S., Smaldone, G., Pedone, E., Luque, F. J., Cabiddu, M. G., Novellino, E., Fowler, C. J., Catalanotti, B., & Onnis, V. (2017). Novel propanamides as fatty acid amide hydrolase inhibitors. European Journal of Medicinal Chemistry, 136, 523-542. https://doi.org/10.1016/j.ejmech.2017.05.033