Discovery and optimization of piperidyl-1,2,3-triazole ureas as potent, selective, and in vivo-active inhibitors of α/β-hydrolase domain containing 6 (ABHD6).
Discovery and optimization of piperidyl-1,2,3-triazole ureas as potent, selective, and in vivo-active inhibitors of α/β-hydrolase domain containing 6 (ABHD6).
复制标题
DOI：
10.1021/jm400899c
复制
发表时间：
2013-11-14
影响因子：
7.3
通讯作者：
Cravatt BF
中科院分区：
文献类型：
--
作者：
Hsu KL;Tsuboi K;Chang JW;Whitby LR;Speers AE;Pugh H;Cravatt BF
α/β-水解酶结构域包含6(ABHD6)是一种跨膜型丝氨酸水解酶，它能降解内源性大麻素2-花生四烯基甘油(2-AG)，从而调节神经系统中某些形式的大麻素受体依赖的信号传导。ABHD6代谢活动和功能的全谱目前尚不清楚，将受益于选择性的体内活性抑制剂。在这里，我们报告了一系列先进的ABHD6不可逆(2-取代)-哌啶基-1，2，3-三氮唑尿素抑制剂的开发和表征，包括化合物KT182和KT203，它们在细胞(<；5 NM)和小鼠(1 mg kg-1)中显示出非凡的效力和选择性，分别作为全身和外周限制性ABHD6抑制剂。我们还描述了一种口服生物可用ABHD6抑制剂KT185，它在体内对其他大脑和肝脏丝氨酸水解酶表现出良好的选择性。因此，我们描述了几种用于ABHD6生物学研究的化学探针，包括脑穿透性和外周限制的抑制剂，它们应该被证明在动物模型中询问ABHD6的功能是有价值的。
Alpha/beta-hydrolase domain containing 6 (ABHD6) is a transmembrane serine hydrolase that hydrolyzes the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) to regulate certain forms of cannabinoid receptor-dependent signaling in the nervous system. The full spectrum of ABHD6 metabolic activities and functions is currently unknown and would benefit from selective, in vivo-active inhibitors. Here, we report the development and characterization of an advanced series of irreversible (2-substituted)-piperidyl-1,2,3-triazole urea inhibitors of ABHD6, including compounds KT182 and KT203, which show exceptional potency and selectivity in cells (< 5 nM) and, at equivalent doses in mice (1 mg kg-1), served as systemic and peripherally-restricted ABHD6 inhibitors, respectively. We also describe an orally-bioavailable ABHD6 inhibitor KT185 that displays excellent selectivity against other brain and liver serine hydrolases in vivo. We thus describe several chemical probes for biological studies of ABHD6, including brain-penetrant and peripherally-restricted inhibitors that should prove of value for interrogating ABHD6 function in animal models.
登录
查看更多内容
影响因子：
25
作者：
Marrs, William R.;Blankman, Jacqueline L.;Horne, Eric A.;Thomazeau, Aurore;Lin, Yi Hsing;Coy, Jonathan;Bodor, Agnes L.;Muccioli, Giulio G.;Hu, Sherry Shu-Jung;Woodruff, Grace;Fung, Susan;Lafourcade, Mathieu;Alexander, Jessica P.;Long, Jonathan Z.;Li, Weiwei;Xu, Cong;Moeller, Thomas;Mackie, Ken;Manzoni, Olivier J.;Cravatt, Benjamin F.;Stella, Nephi
通讯作者：
Stella, Nephi
影响因子：
4.2
作者：
Tchantchou, Flaubert;Zhang, Yumin
通讯作者：
Zhang, Yumin
影响因子：
14.8
作者：
Adibekian, Alexander;Martin, Brent R.;Wang, Chu;Hsu, Ku-Lung;Bachovchin, Daniel A.;Niessen, Sherry;Hoover, Heather;Cravatt, Benjamin F.
通讯作者：
Cravatt, Benjamin F.
影响因子：
--
作者：
Blankman, Jacqueline L.;Simon, Gabriel M.;Cravatt, Benjamin F.
通讯作者：
Cravatt, Benjamin F.
DOI：
10.1073/pnas.1015248108
发表时间：
2011-04-26
影响因子：
11.1
作者：
Bachovchin, Daniel A.;Mohr, Justin T.;Cravatt, Benjamin F.
通讯作者：
Cravatt, Benjamin F.