Synthesis and quantitative structure-activity relationship of fatty acid amide hydrolase inhibitors: modulation at the N-portion of biphenyl-3-yl alkylcarbamates.
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.
Mor
Marco
M
Dipartimento Farmaceutico, Università degli Studi di Parma, Viale G P Usberti 27/A Campus Universitario, I-43100 Parma, Italy.
Lodola
Alessio
A
Rivara
Silvia
S
Vacondio
Federica
F
Duranti
Andrea
A
Tontini
Andrea
A
Sanchini
Silvano
S
Piersanti
Giovanni
G
Clapper
Jason R
JR
King
Alvin R
AR
Tarzia
Giorgio
G
Piomelli
Daniele
D
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry; D006860:Hydrogen Bonding; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001713:Biphenyl Compounds; D002219:Carbamates; D000099252:Fatty Acid Amide Hydrolases; C531074:naphthalen-2-ylmethylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester; C531073:naphthalen-2-ylmethylcarbamic acid biphenyl-3-yl ester