Harnessing the pyrroloquinoxaline scaffold for FAAH and MAGL interaction: definition of the structural determinants for enzyme inhibition

被引：23

作者：

Brindisi, Margherita ^{[1
,2
]}

Brogi, Simone ^{[1
,2
]}

Maramai, Samuele ^{[1
,2
]}

Grillo, Alessandro ^{[1
,2
]}

Borrelli, Giuseppe ^{[1
,2
]}

Butini, Stefania ^{[1
,2
]}

Novellino, Ettore ^{[1
,3
]}

Allara, Marco ^{[4
]}

Ligresti, Alessia ^{[4
]}

Campiani, Giuseppe ^{[1
,2
]}

Di Marzo, Vincenzo ^{[4
]}

Gemma, Sandra ^{[1
,2
]}

机构：

[1] Univ Siena, European Res Ctr Drug Discovery & Dev NatSynDrugs, Via Aldo Moro 2, I-53100 Siena, Italy

[2] Univ Siena, Dipartimento Biotecnol Chim & Farm, Via Aldo Moro 2, I-53100 Siena, Italy

[3] Univ Napoli Federico II, Dipartimento Farm, Via D Montesano 49, I-80131 Naples, Italy

[4] CNR, Inst Biomol Chem, Endocannabinoid Res Grp, Naples, Italy

来源：

RSC ADVANCES | 2016年 / 6卷 / 69期

关键词：

ACID AMIDE HYDROLASE; HIGHLY SELECTIVE INHIBITORS; 5-HT3 RECEPTOR AGONISTS; MONOACYLGLYCEROL LIPASE; ENDOCANNABINOID SYSTEM; DERIVATIVES; BEHAVIOR; DISEASE; PAIN; 2-ARACHIDONOYLGLYCEROL;

D O I：

10.1039/c6ra12524g

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

This paper describes the development of piperazine and 4-aminopiperidine carboxamides/carbamates supported on a pharmacogenic pyrroloquinoxaline scaffold as inhibitors of the endocannabinoid catabolizing enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Structure-activity relationships and molecular modelling studies allowed the definition of the structural requirements for dual FAAH/MAGL inhibition and led to the identification of a small set of derivatives (compounds 5e, i, k, m) displaying a balanced inhibitory profile against both enzymes, with compound 5m being the frontrunner of the subset. Favorable calculated physico-chemical properties suggest further investigation for specific analogues.

引用

页码：64651 / 64664

页数：14

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