Synthesis and Structure–Activity Relationships of FAAH Inhibitors: Cyclohexylcarbamic Acid Biphenyl Esters with Chemical Modulation at the Proximal Phenyl Ring

• DOI: 10.1002/cmdc.200500017
• Publication Date: 2005-11-30T10:18:37Z
• Authors: Giorgio Tarzia; Andrea Duranti; Giuseppe Gatti; Giovanni Piersanti; Andrea Tontini; Silvia Rivara; Alessio Lodola; Pier Vincenzo Plazzi; Marco Mor; Satish Kathuria; Daniele Piomelli
• Keywords: Models, Molecular; 0301 basic medicine; 0303 health sciences; Magnetic Resonance Spectroscopy; Medicinal & Biomolecular Chemistry; Organic Chemistry; Molecular; Quantitative Structure-Activity Relationship; Pharmacology and Pharmaceutical Sciences; 540; Amidohydrolases; Medicinal and Biomolecular Chemistry; 03 medical and health sciences; Models; Benzamides; Carbamates; Enzyme Inhibitors

AbstractFatty 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.