Revisiting 1,3,4-Oxadiazol-2-ones: Utilization in the Development of ABHD6 Inhibitors

被引：10

作者：

Patel, Jayendra Z. ^{[1
]}

van Bruchem, John ^{[1
]}

Laitinen, Tuomo ^{[1
]}

Kaczor, Agnieszka A. ^{[1
,2
]}

Navia-Paldanius, Dina ^{[3
]}

Parkkari, Teija ^{[1
]}

Savinainen, Juha R. ^{[3
]}

Laitinen, Jarmo T. ^{[3
]}

Nevalainen, Tapio J. ^{[1
]}

机构：

[1] Univ Eastern Finland, Fac Hlth Sci, Sch Pharm, FIN-70211 Kuopio, Finland

[2] Med Univ Lublin, Fac Pharm, Dept Synth & Chem Technol Pharmaceut Subst, Div Med Analyt, PL-20093 Lublin, Poland

[3] Univ Eastern Finland, Sch Med, Inst Biomed Physiol, FIN-70211 Kuopio, Finland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 19期

基金：

芬兰科学院;

关键词：

alpha/beta-Hydrolase domain-containing 6; 2-Arachidonoylglycerol; Monoacylglycerol lipase; Fatty acid amide hydrolase; 1,3,4-Oxadiazol-2-ones; ACID AMIDE HYDROLASE; LIPASE INHIBITORS; DOMAIN; 6; SERINE; DISCOVERY; POTENT; TETRAHYDROLIPSTATIN; IDENTIFICATION; OPTIMIZATION; DESIGN;

D O I：

10.1016/j.bmc.2015.08.030

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

This article describes our systematic approach to exploring the utility of the 1,3,4-oxadiazol-2-one scaffold in the development of ABHD6 inhibitors. Compound 3-(3-aminobenzyl)-5-methoxy-1,3,4-oxadiazol-2(3H)-one (JZP-169, 52) was identified as a potent inhibitor of hABHD6, with an IC50 value of 216 nM. This compound at 10 mu M concentration did not inhibit any other endocannabinoid hydrolases, such as FAAH, MAGL and ABHD12, or bind to the cannabinoid receptors (CB1 and CB2). Moreover, in competitive activity-based protein profiling (ABPP), compound 52 (JZP-169) at 10 mu M selectively targeted ABHD6 of the serine hydrolases of mouse brain membrane proteome. Reversibility studies indicated that compound 52 inhibited hABHD6 in an irreversible manner. Finally, homology modelling and molecular docking studies were used to gain insights into the binding of compound 52 to the active site of hABHD6. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：6335 / 6345

页数：11

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