Potent and selective alpha-ketoheterocycle-based inhibitors of the anandamide and oleamide catabolizing enzyme, fatty acid amide hydrolase.
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.
Romero
F Anthony
FA
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Du
Wu
W
Hwang
Inkyu
I
Rayl
Thomas J
TJ
Kimball
F Scott
FS
Leung
Donmienne
D
Hoover
Heather S
HS
Apodaca
Richard L
RL
Breitenbucher
J Guy
JG
Cravatt
Benjamin F
BF
Boger
Dale L
DL
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
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