1.Development of a highly-specific
Zhen CHEN ; Wakana MORI ; Jian RONG ; Michael A SCHAFROTH ; Tuo SHAO ; Richard S VAN ; Daisuke OGASAWARA ; Tomoteru YAMASAKI ; Atsuto HIRAISHI ; Akiko HATORI ; Jiahui CHEN ; Yiding ZHANG ; Kuan HU ; Masayuki FUJINAGA ; Jiyun SUN ; Qingzhen YU ; Thomas L COLLIER ; Yihan SHAO ; Benjamin F CRAVATT ; Lee JOSEPHSON ; Ming-Rong ZHANG ; Steven H LIANG
Acta Pharmaceutica Sinica B 2021;11(6):1686-1695
As a serine hydrolase, monoacylglycerol lipase (MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol (2-AG) in the central nervous system (CNS), leading to the formation of arachidonic acid (AA). Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms, including neuroinflammation, cognitive impairment, epileptogenesis, nociception and neurodegenerative diseases. Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions, and a MAGL positron emission tomography (PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors. Herein, we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates. Pharmacological evaluation of these candidates by activity-based protein profiling identified
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