Structure based design of novel irreversible FAAH inhibitors.
Fatty acid amide hydrolase (FAAH) has attracted significant attention due to its promise as an analgesic target. This has resulted in the discovery of numerous chemical classes as inhibitors of this potential therapeutic target. In this paper we disclose a new series of novel FAAH irreversible azetidine urea inhibitors. In general these compounds illustrate potent activity against the rat FAAH enzyme. Our SAR studies allowed us to optimize this series resulting in the identification of compounds 13 which were potent inhibitors of both human and rat enzyme. This series of compounds illustrated good hydrolase selectivity along with good PK properties.
Wang
Jane L
JL
Pfizer Global Research and Development, 700 Chesterfield PKWY West, Chesterfield, MO 63017, USA. jane.l.wang@pfizer.com
Bowen
Scott J
SJ
Schweitzer
Barbara A
BA
Madsen
Heather M
HM
McDonald
Joseph
J
Pelc
Matthew J
MJ
Tenbrink
Ruth E
RE
Beidler
David
D
Thorarensen
Atli
A
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D014508:Urea / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000700:Analgesics; D001384:Azetidines; D004791:Enzyme Inhibitors; D011724:Pyridazines; D014508:Urea; D000099252:Fatty Acid Amide Hydrolases; C082735:azetidine