1403775-96-1Relevant academic research and scientific papers
In Vitro and in Vivo Evaluation of 11C-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies
Cheng, Ran,Mori, Wakana,Ma, Longle,Alhouayek, Mireille,Hatori, Akiko,Zhang, Yiding,Ogasawara, Daisuke,Yuan, Gengyang,Chen, Zhen,Zhang, Xiaofei,Shi, Hang,Yamasaki, Tomoteru,Xie, Lin,Kumata, Katsushi,Fujinaga, Masayuki,Nagai, Yuji,Minamimoto, Takafumi,Svensson, Mona,Wang, Lu,Du, Yunfei,Ondrechen, Mary Jo,Vasdev, Neil,Cravatt, Benjamin F.,Fowler, Christopher,Zhang, Ming-Rong,Liang, Steven H.
, p. 2278 - 2291 (2018)
Monoacylglycerol lipase (MAGL) is the principle enzyme for metabolizing endogenous cannabinoid ligand 2-arachidonoyglycerol (2-AG). Blockade of MAGL increases 2-AG levels, resulting in subsequent activation of the endocannabinoid system, and has emerged as a novel therapeutic strategy to treat drug addiction, inflammation, and neurodegenerative diseases. Herein we report a new series of MAGL inhibitors, which were radiolabeled by site-specific labeling technologies, including 11C-carbonylation and spirocyclic iodonium ylide (SCIDY) radiofluorination. The lead compound [11C]10 (MAGL-0519) demonstrated high specific binding and selectivity in vitro and in vivo. We also observed unexpected washout kinetics with these irreversible radiotracers, in which in vivo evidence for turnover of the covalent residue was unveiled between MAGL and azetidine carboxylates. This work may lead to new directions for drug discovery and PET tracer development based on azetidine carboxylate inhibitor scaffold.
Azetidinyl oxadiazoles as potent mGluR5 positive allosteric modulators
Packiarajan, Mathivanan,Ferreira, Christine G. Mazza,Hong, Sang-Phyo,White, Andrew D.,Chandrasena, Gamini,Pu, Xiaosui,Brodbeck, Robbin M.,Robichaud, Albert J.
, p. 6469 - 6474 (2012/10/29)
A novel series of aryl azetidinyl oxadiazoles are identified as mGluR5 positive allosteric modulators (PAMs) with improved physico-chemical properties. N-substituted cyclohexyl and exo-norbornyl carboxamides, and carbamate analogs of azetidines are moderate to potent mGluR5 PAMs. The aryl, lower alkyl carboxamides analogs and sulfonamide analogs of azetidines are moderate mGluR5 negative allosteric modulators (NAMs). In the aryl oxadiazole moiety, substituents such as fluoro, chloro and methyl are well tolerated at the meta position while para substituents led to either inactive compounds or NAMs. A tight pharmacophore and subtle 'PAM to NAM switching' with close analogs makes the optimization of the series extremely challenging.
