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 beta-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.

Synthesis and Quantitative Structure-Activity Relationship of Fatty Acid Amide Hydrolase Inhibitors: Modulation at the N-Portion of Biphenyl-3-yl Alkylcarbamates / Mor, Marco; Lodola, Alessio; Rivara, Silvia; Vacondio, Federica; Duranti, A.; Tontini, A.; Sanchini, S.; Piersanti, G.; Clapper, J. R.; King, A. R.; Tarzia, G.; Piomelli, D.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 51:(2008), pp. 3487-3498. [10.1021/jm701631z]

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

MOR, Marco;LODOLA, Alessio;RIVARA, Silvia;VACONDIO, Federica;
2008-01-01

Abstract

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 beta-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.
2008
Synthesis and Quantitative Structure-Activity Relationship of Fatty Acid Amide Hydrolase Inhibitors: Modulation at the N-Portion of Biphenyl-3-yl Alkylcarbamates / Mor, Marco; Lodola, Alessio; Rivara, Silvia; Vacondio, Federica; Duranti, A.; Tontini, A.; Sanchini, S.; Piersanti, G.; Clapper, J. R.; King, A. R.; Tarzia, G.; Piomelli, D.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 51:(2008), pp. 3487-3498. [10.1021/jm701631z]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/1833022
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