The development of potent and selective inhibitors of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of oleamide (an endogenous sleep-inducing lipid) and anandamide (an endogenous ligand for cannabinoid and vanilloid receptors), is detailed. The studies will provide not only the in vitro characterization of the inhibitors, but also their in vivo evaluation (pain, sleep, and inflammation) and characterization (PK properties, metabolism). They will clarify the role of endogenous oleamide and anandamide, establish the full scope of the utility of FAAH as a therapeutic target, and provide some of the first clinical candidates for the treatment of pain, sleep disorders, and chronic inflammatory diseases including contact dermatitis, and multiple sclerosis. Our studies have been extensive, providing the first class of selective, exceptionally potent, reversible and competitive inhibitors of FAAH and defining key structural features that impact inhibitor design. These studies not only provided a set of efficacious ?-ketoheterocycle FAAH inhibitors, but they addressed all the objectives set forth as specific aims in the prior grant period. The simultaneous potency (against FAAH) and selectivity (ABPP proteome-wide screening) optimizations provided selective inhibitors that display no significant off target activity including other potential enzyme targets, common P450 metabolizing enzymes, or hERG, and that exhibit efficacious in vivo activity in all models of chronic and neuropathic pain and inflammation. The continuation of these studies, their extensions to new classes of FAAH inhibitors, their in vitro and in vivo optimization using fundamental chemical, biochemical, and pharmacological tools, will be conducted with the intention of providing the first reversible inhibitors for examination in the clinic. In addition, studies to define the sites of action and endogenous role of every fatty acid amide signaling molecule and to prepare and utilize a screening library to annotate every uncharacterized serine hydrolase will be conducted.

Public Health Relevance

The development and characterization of inhibitors of the enzyme fatty acid amide hydrolase (FAAH) will be pursued and could provide a new treatment for chronic and neuropathic pain. The discovery and characterization of new endogenous signaling fatty acid amides and their sites of action would provide a fundamental understanding of their physiological role and new opportunities for therapeutic intervention in a range of disorders (sleep, feeding, anxiety). The development of selective and potent inhibitors for each unannotated serine hydrolase will facilitate the delineation of their endogenous role and their evaluation as new therapeutic targets.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Rapaka, Rao
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Janssen, Freek J; Baggelaar, Marc P; Hummel, Jessica J A et al. (2015) Comprehensive Analysis of Structure-Activity Relationships of α-Ketoheterocycles as sn-1-Diacylglycerol Lipase α Inhibitors. J Med Chem 58:9742-53
Otrubova, Katerina; Cravatt, Benjamin F; Boger, Dale L (2014) Design, synthesis, and characterization of α-ketoheterocycles that additionally target the cytosolic port Cys269 of fatty acid amide hydrolase. J Med Chem 57:1079-89
Duncan, Katharine K; Otrubova, Katerina; Boger, Dale L (2014) α-Ketoheterocycle inhibitors of fatty acid amide hydrolase: exploration of conformational constraints in the acyl side chain. Bioorg Med Chem 22:2763-70
Otrubova, Katerina; Srinivasan, Venkat; Boger, Dale L (2014) Discovery libraries targeting the major enzyme classes: the serine hydrolases. Bioorg Med Chem Lett 24:3807-13
Otrubova, Katerina; Brown, Monica; McCormick, Michael S et al. (2013) Rational design of fatty acid amide hydrolase inhibitors that act by covalently bonding to two active site residues. J Am Chem Soc 135:6289-99
Booker, Lamont; Kinsey, Steven G; Abdullah, Rehab A et al. (2012) The fatty acid amide hydrolase (FAAH) inhibitor PF-3845 acts in the nervous system to reverse LPS-induced tactile allodynia in mice. Br J Pharmacol 165:2485-96
Otrubova, Katerina; Boger, Dale L (2012) α-Ketoheterocycle-based Inhibitors of Fatty Acid Amide Hydrolase (FAAH). ACS Chem Neurosci 3:340-348
Mileni, Mauro; Garfunkle, Joie; Ezzili, Cyrine et al. (2011) Fluoride-mediated capture of a noncovalent bound state of a reversible covalent enzyme inhibitor: X-ray crystallographic analysis of an exceptionally potent α-ketoheterocycle inhibitor of fatty acid amide hydrolase. J Am Chem Soc 133:4092-100
Ezzili, Cyrine; Mileni, Mauro; McGlinchey, Nicholas et al. (2011) Reversible competitive ýý-ketoheterocycle inhibitors of fatty acid amide hydrolase containing additional conformational constraints in the acyl side chain: orally active, long-acting analgesics. J Med Chem 54:2805-22
Otrubova, Katerina; Ezzili, Cyrine; Boger, Dale L (2011) The discovery and development of inhibitors of fatty acid amide hydrolase (FAAH). Bioorg Med Chem Lett 21:4674-85

Showing the most recent 10 out of 25 publications