title: Potent and selective alpha-ketoheterocycle-based inhibitors of the anandamide and oleamide catabolizing enzyme, fatty acid amide hydrolase.
abstract: A study of the structure-activity relationships (SAR) of 2f (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed, targeting the 5-position of the oxazole. Examination of a series of substituted benzene derivatives (12-14) revealed that the optimal position for substitution was the meta-position with selected members approaching or exceeding the potency of 2f. Concurrent with these studies, the effect of substitution on the pyridine ring of 2f was also examined. A series of small, nonaromatic C5-substituents was also explored and revealed that the K(i) follows a well-defined correlation with the Hammett sigma(p) constant (rho = 3.01, R2 = 0.91) in which electron-withdrawing substituents enhance potency, leading to inhibitors with K(i)s as low as 400 pM (20n). Proteomic-wide screening of the inhibitors revealed that most are exquisitely selective for FAAH over all other mammalian proteases, reversing the 100-fold preference of 20a (C5 substituent = H) for the enzyme TGH.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: F Anthony
authors.initials: FA
authors.lastname: Romero
authors.forename: Wu
authors.initials: W
authors.lastname: Du
authors.forename: Inkyu
authors.initials: I
authors.lastname: Hwang
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rayl
authors.forename: F Scott
authors.initials: FS
authors.lastname: Kimball
authors.forename: Donmienne
authors.initials: D
authors.lastname: Leung
authors.forename: Heather S
authors.initials: HS
authors.lastname: Hoover
authors.forename: Richard L
authors.initials: RL
authors.lastname: Apodaca
authors.forename: J Guy
authors.initials: JG
authors.lastname: Breitenbucher
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019556:COS Cells; D002522:Chlorocebus aethiops; D063388:Endocannabinoids; D006801:Humans; D009829:Oleic Acids / Q000378:metabolism*; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D040901:Proteomics; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D001555:Benzene Derivatives; D063388:Endocannabinoids; D009829:Oleic Acids; D010080:Oxazoles; D053284:Polyunsaturated Alkamides; D011994:Recombinant Proteins; D000099252:Fatty Acid Amide Hydrolases; C029407:oleylamide; C078814:anandamide