title: Synthesis and structure-activity relationships of FAAH inhibitors: cyclohexylcarbamic acid biphenyl esters with chemical modulation at the proximal phenyl ring.
abstract: Fatty acid amide hydrolase (FAAH) is a serine hydrolase that catalyzes the intracellular hydrolysis of fatty acid ethanolamides such as anandamide and oleoylethanolamide. Targeting this enzyme may have important therapeutic potentials owing to the multiple physiological roles of these amides. Cyclohexylcarbamic acid biphenyl-3-yl ester (URB524) was one of the most promising FAAH inhibitors so far described. We report the modulation of the electronic and steric features of the proximal phenyl ring of this compound by introducing a series of substituents at the ortho and para positions. pIC50 values were found to correlate with molecular features thought to be involved in the recognition step such as steric hindrance and hydrogen-bonding ability. Derivatives with small polar groups at the para position of the proximal phenyl ring were slightly better FAAH inhibitors than the parent compound URB524.
authors.affiliation: Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Urbino Carlo Bo, Piazza del Rinascimento 6, 61029 Urbino, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.forename: Andrea
authors.initials: A
authors.lastname: Duranti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gatti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Piersanti
authors.forename: Andrea
authors.initials: A
authors.lastname: Tontini
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
authors.forename: Pier Vincenzo
authors.initials: PV
authors.lastname: Plazzi
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Satish
authors.initials: S
authors.lastname: Kathuria
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D001549:Benzamides / Q000737:chemistry*; D002219:Carbamates / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001549:Benzamides; D002219:Carbamates; D004791:Enzyme Inhibitors; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester