Benzothiophene piperazine and piperidine urea inhibitors of fatty acid amide hydrolase (FAAH).
The synthesis and structure-activity relationships (SAR) of a series of benzothiophene piperazine and piperidine urea FAAH inhibitors is described. These compounds inhibit FAAH by covalently modifying the enzyme's active site serine nucleophile. Activity-based protein profiling (ABPP) revealed that these urea inhibitors were completely selective for FAAH relative to other mammalian serine hydrolases. Several compounds showed in vivo activity in a rat complete Freund's adjuvant (CFA) model of inflammatory pain.
Johnson
Douglas S
DS
Pfizer Global Research and Development, Ann Arbor, MI 48105, USA. doug.johnson@pfizer.com
Ahn
Kay
K
Kesten
Suzanne
S
Lazerwith
Scott E
SE
Song
Yuntao
Y
Morris
Mark
M
Fay
Lorraine
L
Gregory
Tracy
T
Stiff
Cory
C
Dunbar
James B
JB
Liimatta
Marya
M
Beidler
David
D
Smith
Sarah
S
Nomanbhoy
Tyzoon K
TK
Cravatt
Benjamin F
BF
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008956:Models, Chemical; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D010879:Piperazines; D010880:Piperidines; D013876:Thiophenes; D014508:Urea; D000099252:Fatty Acid Amide Hydrolases; C088015:benzothiophene