title: A second generation of carbamate-based fatty acid amide hydrolase inhibitors with improved activity in vivo.
abstract: The fatty acid ethanolamides are a class of signaling lipids that include agonists at cannabinoid and alpha type peroxisome proliferator-activated receptors (PPARalpha). In the brain, these compounds are primarily hydrolyzed by the intracellular serine enzyme fatty acid amide hydrolase (FAAH). O-aryl carbamate FAAH inhibitors such as URB597 are being evaluated clinically for the treatment of pain and anxiety, but interactions with carboxylesterases in liver might limit their usefulness. Here we explore two strategies aimed at overcoming this limitation. Lipophilic N-terminal substitutions, which enhance FAAH recognition, yield potent inhibitors but render such compounds susceptible to attack by broad-spectrum hydrolases and inactive in vivo. By contrast, polar electron-donating O-aryl substituents, which decrease carbamate reactivity, yield compounds, such as URB694, that are highly potent FAAH inhibitors in vivo and less reactive with off-target carboxylesterases. The results suggest that an approach balancing inhibitor reactivity with target recognition produces FAAH inhibitors that display significantly improved drug-likeness.
authors.affiliation: Departments of Pharmacology and Biological Chemistry, 360 MSRII, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Clapper
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.forename: Alvin R
authors.initials: AR
authors.lastname: King
authors.forename: Andrea
authors.initials: A
authors.lastname: Duranti
authors.forename: Andrea
authors.initials: A
authors.lastname: Tontini
authors.forename: Claudia
authors.initials: C
authors.lastname: Silva
authors.forename: Silvano
authors.initials: S
authors.lastname: Sanchini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D002219:Carbamates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D043182:Carboxylesterase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006207:Half-Life; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001713:Biphenyl Compounds; D002219:Carbamates; D043182:Carboxylesterase; D004791:Enzyme Inhibitors; D000099252:Fatty Acid Amide Hydrolases; C475427:cyclohexylcarbamic acid biphenyl-3-yl ester