Biaryl tetrazolyl ureas as inhibitors of endocannabinoid metabolism: Modulation at the N-portion and distal phenyl ring

被引：15

作者：

Ortar, Giorgio ^{[1
]}

Morera, Enrico ^{[1
]}

De Petrocellis, Luciano ^{[2
]}

Ligresti, Alessia ^{[3
]}

Moriello, Aniello Schiano ^{[2
]}

Morera, Ludovica ^{[1
]}

Nalli, Marianna ^{[1
]}

Ragno, Rino ^{[1
,4
]}

Pirolli, Adele ^{[1
,4
]}

Di Marzo, Vincenzo ^{[3
]}

机构：

[1] Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farm, I-00185 Rome, Italy

[2] CNR, Ist Cibernet, Endocannabinoid Res Grp, I-80078 Naples, Italy

[3] CNR, Ist Chim Biomol, Endocannabinoid Res Grp, I-80078 Naples, Italy

[4] Univ Roma La Sapienza, RCMD, I-00185 Rome, Italy

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 63卷

关键词：

Endocannabinoids; Fatty acid amide hydrolase (FAAH); Monoacylglycerol lipase (MAGL); TRPV1; channel; TRPA1; Biaryl tetrazolyl ureas; ACID AMIDE HYDROLASE; MONOACYLGLYCEROL LIPASE; MEDICINAL CHEMISTRY; COVALENT INHIBITORS; POTENT INHIBITOR; ANANDAMIDE; DISCOVERY; SYSTEM; FAAH; TARGETS;

D O I：

10.1016/j.ejmech.2013.02.005

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In the present study, we have further extended the structure activity relationships for the tetrazolyl ureas class of compounds as potential FAAH and/or MAGL inhibitors, by replacing the dimethylamino group of the parent compounds 1 and 2 with bulkier groups or by introducing on the distal phenyl ring of 1 and 2 a selected set of substituents. Some of the new compounds (16, 20, 21, 25, and 28) inhibited FAAH potently (IC50 = 3.0-9.7 nM) and selectively (39- to more than 141-fold) over MAGL, while tetrazole 27 turned out to be a promising dual FAAH MAGL inhibitor of potential therapeutic use. Covalent docking studies on FAAH indicated that the binding modes of tetrazoles 1-32 did not display a unique pattern. The ability of tetrazoles 1-32 to act as TRPV1 and TRPA1 modulators was also investigated. (C) 2013 Elsevier Masson SAS. All rights reserved.

引用

页码：118 / 132

页数：15

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