Discovery of a potent, selective, and efficacious class of reversible α-ketoheterocycle inhibitors of fatty acid amide hydrolase effective as analgesics

Dale L. Boger, Hiroshi Miyauchi, Wu Du, Christophe Hardouin, Robert A. Fecik, Heng Cheng, Inkyu Hwang, Michael P. Hedrick, Donmienne Leung, Orlando Acevedo, Cristiano R.W. Guimarães, William L. Jorgensen, Benjamin F. Cravatt

Research output: Contribution to journalArticlepeer-review

190 Scopus citations

Abstract

Fatty acid amide hydrolase (FAAH) degrades neuromodulating fatty acid amides including anandamide (endogenous cannabinoid agonist) and oleamide (sleep-inducing lipid) at their sites of action and is intimately involved in their regulation. Herein we report the discovery of a potent, selective, and efficacious class of reversible FAAH inhibitors that produce analgesia in animal models validating a new therapeutic target for pain intervention. Key to the useful inhibitor discovery was the routine implementation of a proteomics-wide selectivity screen against the serine hydrolase superfamily ensuring selectivity for FAAH coupled with systematic in vivo examinations of candidate inhibitors.

Original languageEnglish (US)
Pages (from-to)1849-1856
Number of pages8
JournalJournal of medicinal chemistry
Volume48
Issue number6
DOIs
StatePublished - Mar 24 2005

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