Synthesis and structure-activity relationships of ionizable 1,3,4-oxadiazol-2(3H)-ones as peripherally selective FAAH inhibitors with improved aqueous solubility

被引：3

作者：

Beliaev, Alexandre ^{[1
]}

Ferreira, Humberto S. ^{[1
]}

Learmonth, David A. ^{[2
]}

Bonifacio, Maria Joao ^{[3
]}

Torrao, Leonel ^{[3
]}

Pires, Nuno M. ^{[3
]}

Soares-da-Silva, Patricio ^{[3
,4
]}

Kiss, Laszlo E. ^{[1
]}

机构：

[1] BIAL Portela & Ca SA, Dept Res & Dev, Chem Lab, Coronado, S Romao E S Man, Portugal

[2] Stemmatters Biotecnol & Med Regenerat SA, P-4805017 Guimaraes, Portugal

[3] BIAL Portela & Ca SA, Dept Res & Dev, Pharmacol Lab, Coronado, S Romao E S Man, Portugal

[4] Univ Porto, Fac Med, Dept Pharmacol & Therapeut, P-4200319 Oporto, Portugal

来源：

PURE AND APPLIED CHEMISTRY | 2016年 / 88卷 / 04期

关键词：

aqueous solubility; ESOC-19; FAAH inhibitors; fatty acid amide hydrolase; 1,3,4-oxadiazol-2(3H)-ones; peripheral selectivity; ACID AMIDE HYDROLASE; MONOACYLGLYCEROL LIPASE INHIBITORS; THERAPEUTIC TARGET; ANTAGONISTS; ENZYME; DESIGN;

D O I：

10.1515/pac-2016-0104

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Novel 5-(2,4-difluorophenoxy)-3-aryl-1,3,4-oxadiazol-2(3H)-ones were prepared and in vivo SAR are discussed. Ionisable substituents on the N-phenyl ring provided compounds with significantly improved aqueous solubility. In addition, these analogues retained equivalent or improved potency against FAAH enzyme compared to the parent phenols 2-3. FAAH inhibition by the 2-(piperazin-1-yl) ethyl and 3-(piperazin-1-yl) propyl derivatives 24 and 30 was confined to the periphery in mice (30 mg/kg), whereas hepatic FAAH activity was inhibited by over 90 %.

引用

页码：341 / 347

页数：7

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