Synthesis and Quantitative Structure−Activity Relationship of Fatty Acid Amide Hydrolase Inhibitors: Modulation at the N-Portion of Biphenyl-3-yl Alkylcarbamates

详细信息    查看全文

• 作者：Marco Mor ; Alessio Lodola ; Silvia Rivara ; Federica Vacondio ; Andrea Duranti ; Andrea Tontini ; Silvano Sanchini ; Giovanni Piersanti ; Jason R. Clapper ; Alvin R. King ; Giorgio Tarzia ; Daniele Piomelli
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：June 26, 2008
• 年：2008
• 卷：51
• 期：12
• 页码：3487 - 3498
• 全文大小：883K
• 年卷期：v.51,no.12(June 26, 2008)
• ISSN：1520-4804

文摘

Alkylcarbamic acid biphenyl-3-yl esters are a class of fatty acid amide hydrolase (FAAH) inhibitors that comprises cyclohexylcarbamic acid 3′-carbamoylbiphenyl-3-yl ester (URB597), a compound with analgesic, anxiolytic-like and antidepressant-like properties in rat and mouse models. Here, we extended the structure−activity relationships (SARs) for this class of compounds by replacing the cyclohexyl ring of the parent compound cyclohexylcarbamic acid biphenyl-3-yl ester (URB524) (FAAH IC₅₀ = 63 nM) with a selected set of substituents of different size, shape, flexibility, and lipophilicity. Docking experiments and linear interaction energy (LIE) calculations indicated that the N-terminal group of O-arylcarbamates fits within the lipophilic region of the substrate-binding site, mimicking the arachidonoyl chain of anandamide. Significant potency improvements were observed for the β-naphthylmethyl derivative 4q (IC₅₀ = 5.3 nM) and its 3′-carbamoylbiphenyl-3-yl ester 4z (URB880, IC₅₀ = 0.63 nM), indicating that shape complementarity and hydrogen bonds are crucial to obtain highly potent inhibitors.