Design, Synthesis, and Structure−Activity Relationships of Alkylcarbamic Acid Aryl Esters, a New Class of Fatty Acid Amide Hydrolase Inhibitors

• DOI: 10.1021/jm021119g
• Publication Date: 2003-05-29T09:39:38Z
• Authors: Giorgio Tarzia; Andrea Duranti; Andrea Tontini; Giovanni Piersanti; Marco Mor; Silvia Rivara; Pier Vincenzo Plazzi; Chris Park; Satish Kathuria; Daniele Piomelli
• Keywords: Anandamide; Palmitoylethanolamide; Serine hydrolase; Amide

Fatty acid amide hydrolase (FAAH), an intracellular serine enzyme, participates in the deactivation of fatty ethanolamides such as endogenous cannabinoid anandamide, intestinal satiety factor oleoylethanolamide, and peripheral analgesic anti-inflammatory palmitoylethanolamide. In present study, we report on design, synthesis, structure−activity relationships (SAR) a novel class potent, selective, systemically active inhibitors FAAH activity, which have recently shown to exert potent anxiolytic-like effects rats. These compounds are characterized by carbamic template substituted with alkyl or aryl groups at their O- N-termini. Most inhibit FAAH, but not several other hydrolases, potencies that depend size shape substituents. Initial SAR investigations suggested requirements for optimal potency lipophilic N-alkyl substituent (such n-butyl cyclohexyl) bent O-aryl substituent. Furthermore, group is essential activity. A 3D-QSAR analysis alkylcarbamic esters showed moiety correlated inhibitory potency. CoMSIA model was constructed, indicating whereas steric occupation area corresponding meta position O-phenyl ring improves potency, region low tolerance enzyme site exists para same ring. The moieties best fit surface closely resembles folded conformations observed complexes unsaturated acids different proteins. URB524 (N-cyclohexylcarbamic biphenyl-3-yl ester, 9g) most compound series (IC50 = 63 nM) therefore selected further optimization.