N-aryl 2-aryloxyacetamides as a new class of fatty acid amide hydrolase (FAAH) inhibitors

Abstract

Fatty acid amide hydrolase (FAAH) is a promising target for the development of drugs to treat neurological diseases. In search of new FAAH inhibitors, we identified 2-(4-cyclohexylphenoxy)-N-(3-(oxazolo[4,5-b]pyridin-2-yl)phenyl)acetamide, 4g, with an IC₅₀ of 2.6 µM as a chemical starting point for the development of potent FAAH inhibitors. Preliminary hit-to-lead optimisation resulted in 2-(4-phenylphenoxy)-N-(3-(oxazolo[4,5-b]pyridin-2-yl)phenyl)acetamide, 4i, with an IC₅₀ of 0.35 µM.

Keywords:

• Fatty acid amide hydrolase inhibitors
• endocannabinoid system
• oxazolo[4,5-b]pyridine anilines
• 1H-imidazo[4,5-b]pyridine anilines

Acknowledgements

This work was supported by Umeå Centre for Microbial Research (UCMR), Umeå, Molecular Infection Medicine Sweden (MIMS), Umeå, the Knut & Alice Wallenberg foundation, the Swedish Research Council (for M.E.). The authors would like to acknowledge the Swedish National Infrastructure for Computing (SNIC) and the High Performance Computing Centre North (HPC2N) for computational resources and technical support.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

Knut och Alice Wallenbergs Stiftelse, 10.13039/501100004063 [2008.0064]; Vetenskapsrådet, 10.13039/501100004359 [521-2012-2802].