Inhibitors of Fatty Acid Amide Hydrolase
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 5 1067
(41) Cravatt, B. F.; Demarest, K.; Patricelli, M. P.; Bracey, M. H.; Giang,
D. K.; Martin, B. R.; Lichtman, A. H. Supersensitivity to Anandamide
and Enhanced Endogenous Cannabinoid Signaling in Mice Lacking
Fatty Acid Amide Hydrolase. Proc. Natl. Acad. Sci. U.S.A. 2001,
98, 9371-9376.
(42) Cravatt, B. F.; Saghatelian, A.; Hawkins, E. G.; Clement, A. B.;
Bracey, M. H.; Lichtman, A. H. Functional Disassociation of the
Central and Peripheral Fatty Acid Amide Signaling Systems. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 10821-10826.
(43) Lichtman, A. H.; Shelton, C. C.; Advani, T.; Cravatt, B. F. Mice
Lacking Fatty Acid Amide Hydrolase Exhibit a Cannabinoid Recep-
tor-Mediated Phenotypic Hypoalgesia. Pain 2004, 109, 319-
327.
(44) Cravatt, B. F.; Lichtman, A. H. Fatty Acid Amide Hydrolase: An
Emerging Therapeutic Target in the Endocannabinoid System. Curr.
Opin. Chem. Biol. 2003, 7, 469-475.
(45) Boger, D. L.; Miyauchi, H.; Du, W.; Hardouin, C.; Fecik, R. A.;
Cheng, H.; Hwang, I.; Hedrick, M. P.; Leung, D.; Acevedo, O.;
Guimara´es, C. R. W.; Jorgensen, W. L.; Cravatt, B. F. Discovery of
a Potent, Selective, and Efficacious Class of Reversible R-Ketohet-
erocycle Inhibitors of Fatty Acid Amide Hydrolase as Analgesics.
J. Med. Chem. 2005, 48, 1849-1856.
(46) Boger, D. L.; Sato, H.; Lerner, A. E.; Austin, B. J.; Patterson, J. E.;
Patricelli, M. P.; Cravatt, B. F. Trifluoromethyl Ketone Inhibitors of
Fatty Acid Amide Hydrolase: A Probe of Structural and Confor-
mational Features Contributing to Inhibition. Bioorg. Med. Chem.
Lett. 1999, 9, 265-270.
(47) Boger, D. L.; Sato, H.; Lerner, A. E.; Hedrick, M. P.; Fecik, R. A.;
Miyauchi, H.; Wilkie, G. D.; Austin, B. J.; Patricelli, M. P.; Cravatt,
B. F. Exceptionally Potent Inhibitors of Fatty Acid Amide Hydro-
lase: The Enzyme Responsible for Degradation of Endogenous
Oleamide and Anandamide. Proc. Natl. Acad. Sci. U.S.A. 2000, 97,
5044-5049.
(48) De Petrocellis, L.; Melck, D.; Ueda, N.; Maurelli, S.; Kurahashi, Y.;
Yamamoto, S.; Marino, G.; Di Marzo, V. Novel Inhibitors of Brain,
Neuronal, and Basophilic Anandamide Amidohydrolase. Biochem.
Biophys. Res. Commun. 1997, 231, 82-88.
(49) Deutsch, D. G.; Omeir, R.; Arreaza, G.; Salehani, D.; Prestwich, G.
D.; Huang, Z.; Howlett, A. Methyl Arachidonyl Fluorophospho-
nate: A Potent Irreversible Inhibitor of Anandamide Amidase.
Biochem. Pharmacol. 1997, 53, 255-260.
(50) Deutsch, D. G.; Lin, S.; Hill, W. A. G.; Morse, K. L.; Salehani, D.;
Arreaza, G.; Omeir, R. L.; Makriyannis, A. Fatty Acid Sulfonyl
Fluorides Inhibit Anandamide Metabolism and Bind to the Cannab-
inoid Receptor. Biochem. Biophys. Res. Commun. 1997, 231, 217-
221.
(51) Du, W.; Hardouin, C.; Cheng, H.; Hwang, I.; Boger, D. L.
Heterocyclic Sulfoxide and Sulfone Inhibitors of Fatty Acid Amide
Hydrolase. Bioorg. Med. Chem. Lett. 2005, 15, 103-106.
(52) Edgemond, W. S.; Greenberg, M. J.; McGinley, P. J.; Muthians, S.;
Campbell, W. B.; Hillard, C. J. Synthesis and Characterization of
Diazomethylarachidonyl Ketone: An Irreversible Inhibitor of N-
Arachidonylethanolamine Amidohydrolase. J. Pharmacol. Exp. Ther.
1998, 286, 184-190.
(53) Fernando, S. R.; Pertwee, R. G. Evidence that Methyl Arachidonyl
Fluorophosphonate is an Irreversible Cannabinoid Receptor Antago-
nist. Br. J. Pharmacol. 1997, 121, 1716-1720.
(54) Koutek, B.; Prestwich, G. D.; Howlett, A. C.; Chin, S. A.; Salehani,
D.; Akhavan, N.; Deutsch, D. G. Inhibitors of Arachidonoyl
Ethanolamide Hydrolysis. J. Biol. Chem. 1994, 269.
(55) Patricelli, M. P.; Patterson, J. P.; Boger, D. L.; Cravatt, B. F. An
Endogenous Sleep-Inducing Compound is a Novel Competitive
Inhibitor of Fatty Acid Amide Hydrolase. Bioorg. Med. Chem. Lett.
1998, 8, 613-618.
(56) Patterson, J. E.; Ollmann, I. R.; Cravatt, B. F.; Boger, D. L.; Wong,
C.-H.; Lerner, R. A. Inhibition of Oleamide Hydrolase Catalyzed
Hydrolysis of the Endogenous Sleep-Inducing Lipid cis-9-Octade-
cenamide. J. Am. Chem. Soc. 1996, 118, 5938-5945.
(59) Mor, M.; Rivara, S.; Lodola, A.; Plazzi, P. V.; Tarzia, G.; Duranti,
A.; Tontini, A.; Piersanti, G.; Kathuria, S.; Piomelli, D. Cyclohexy-
lcarbamic Acid 3′- or 4′-Substituted Biphenyl-3-yl Esters as Fatty
Acid Amide Hydrolase Inhibitors: Synthesis, Quantitative Structure-
Activity Relationships, and Molecular Modeling Studies. J. Med.
Chem. 2004, 47, 4998-5008.
(60) Muccioli, G. G.; Fazio, N.; Scriba, G. K. E.; Poppitz, W.; Cannata,
F.; Poupaert, J. H.; Wouters, J.; Lambert, D. M. Substituted
2-Thioxoimidazolidin-4-ones and Imidazolidine-2,4-diones as Fatty
Acid Amide Hydrolase Inhibitors Templates. J. Med. Chem. 2006,
49, 417-425.
(61) Romero, F. A.; Hwang, I.; Boger, D. L. Delineation of a Fundamental
R-Ketoheterocycle Substituent Effect For Use in the Design of
Enzyme Inhibitors. J. Am. Chem. Soc. 2006, 128, 14004-14005.
(62) Leung, D.; Du, W.; Hardouin, C.; Cheng, H.; Hwang, I.; Cravatt, B.
F.; Boger, D. L. Discovery of an Exceptionally Potent and Selective
Class of Fatty Acid Amide Hydrolase Inhibitors Enlisting Proteome-
Wide Selectivity Screening: Concurrent Optimization of Enzyme
Inhibitor Potency and Selectivity. Bioorg. Med. Chem. Lett. 2005,
15, 1423-1428.
(63) Hohmann, A. G.; Suplita, R. L.; Bolton, N. M.; Neeley, M. H.;
Fegley, D.; Mangieri, R.; Krey, J.; Walker, J. M.; Holmes, P. V.;
Crystal, J. D.; Duranti, A.; Tontini, A.; Mor, M.; Tarzia, G.; Piomelli,
D. An Endocannabinoid Mechanism for Stress-Induced Analgesia.
Nature 2005, 435, 1108-1112.
(64) Alexander, J. P.; Cravatt, B. F. The Putative Endocannabinoid
Transport Blocker LY2183240 Is a Potent Inhibitor of FAAH and
Several Other Brain Serine Hydrolases. J. Am. Chem. Soc. 2006,
128, 9699-9704.
(65) Alexander, J. P.; Cravatt, B. F. Mechanism of Carbamate Inactivation
of FAAH: Implications for the Design of Covalent Inhibitors and
In Vivo Functional Probes for Enzymes. Chem. Biol. 2005, 12, 1179-
1187.
(66) Lichtman, A. H.; Leung, D.; Shelton, C. C.; Saghatelian, A.;
Hardouin, C.; Boger, D. L.; Cravatt, B. F. Reversible Inhibitors of
Fatty Acid Amide Hydrolase that Promote Analgesia: Evidence for
an Unprecedented Combination of Potency and Selectivity. J.
Pharmacol. Exp. Ther. 2004, 311, 441-448.
(67) Boger, D. L.; Miyauchi, H.; Hedrick, M. P. R-Keto Heterocycle
Inhibitors of Fatty Acid Amide Hydrolase: Carbonyl Group Modi-
fication and R-Substitution. Bioorg. Med. Chem. Lett. 2001, 11,
1517-1520.
(68) Chang, L.; Luo, L.; Palmer, J. A.; Sutton, S.; Wilson, S. J.; Barbier,
A. J.; Breitenbucher, J. G.; Chaplan, S. R.; Webb, M. Inhibition of
Fatty Acid Amide Hydrolase Produces Analgesia by Multiple
Mechanisms. Br. J. Pharmacol. 2006, 148, 102-113.
(69) Leung, D.; Hardouin, C.; Boger, D. L.; Cravatt, B. F. Discovering
Potent and Selective Reversible Inhibitors of Enzymes in Complex
Proteomes. Nature Biotechnol. 2003, 21, 687-691.
(70) Vedejs, E.; Monahan, S. D. Metalation of Oxazole-Borane Com-
plexes: A Practical Solution to the Problem of Electrocyclic Ring
Opening of 2-Lithiooxazoles. J. Org. Chem. 1996, 61, 5192-
5193.
(71) Hari, Y.; Obika, S.; Sakaki, M.; Morio, K.; Yamagata, Y.; Imanishi,
T. Effective Synthesis of C-Nucleosides with 2′,4′-BNA Modification.
Tetrahedron 2002, 58, 3051-3063.
(72) Farina, V.; Krishnamurthy, V.; Scott, W. J. The Stille Reaction. Org.
React. 1997, 50, 1-652.
(73) Dess, D. B.; Martin, J. C. A Useful 12-I-5 Triacetoxyperiodinane
(the Dess-Martin periodinane) for the Selective Oxidation of Primary
or Secondary Alcohols and a Variety of Related 12-I-5 Species. J.
Am. Chem. Soc. 1991, 113, 7277-7287.
(74) Chen, Q.-Y.; Wu, S.-W. Methyl Fluorosulphonyldifluoroacetate; A
New Trifluoromethylating Agent. J. Chem. Soc., Chem. Commun.
1989, 705-706.
(75) Qing, F.-L.; Fan, J.; Sun, H.-B.; Yue, X.-J. First Synthesis of ortho-
Trifluoromethylated Aryl Triflates. J. Chem. Soc., Perkin Trans. 1
1997, 3053-3057.
(76) Patricelli, M. P.; Lashuel, H. A.; Giang, D. K.; Kelly, J. W.; Cravatt,
B. F. Comparative Characterization of a Wild Type and Transmem-
brane Domain-Deleted Fatty Acid Amide Hydrolase: Identification
of the Transmembrane Domain as a Site for Oligomerization.
Biochemistry 1998, 37, 15177-15187.
(57) Tarzia, G.; Duranti, A.; Gatti, G.; Piersanti, G.; Tontini, A.; Rivara,
S.; Lodola, A.; Plazzi, P. V.; Mor, M.; Kathuria, S.; Piomelli, D.
Synthesis and Structure-Activity Relationships of FAAH Inhibi-
tors: Cyclohexylcarbamic Acid Biphenyl Esters with Chemical
Modulation at the Proximal Phenyl Ring. ChemMedChem 2006, 1,
130-139.
(58) Tarzia, G.; Duranti, A.; Tontini, A.; Piersanti, G.; Mor, M.; Rivara,
S.; Plazzi, P. V.; Park, C.; Kathuria, S.; Piomelli, D. Design,
Synthesis, and Structure-Activity Relationships of Alkylcarbamic
Acid Aryl Esters, a New Class of Fatty Acid Amide Hydrolase
Inhibitors. J. Med. Chem. 2003, 46, 2352-2360.
(77) Guimara´es, C. R. W.; Boger, D. L.; Jorgensen, W. L. Elucidation of
Fatty Acid Amide Hydrolase Inhibition by Potent R-Ketoheterocycle
Derivatives from Monte Carlo Simulations. J. Am. Chem. Soc. 2005,
127, 17377-17384.
(78) Edwards, P. D.; Zottola, M. A.; Davis, M.; Williams, C. M.; Tuthill,
P. A. Peptidyl R-Ketoheterocyclic Inhibitors of Human Neutrophil
Elastase. 3. In Vitro Potency and in Vivo Potency of a Series of
Peptidyl R-Ketobenzoxazoles. J. Med. Chem. 1995, 38, 3972-
3982.