Tetrahydrolipstatin analogues as modulators of endocannabinoid 2-arachidonoylglycerol metabolism

G Ortar, T Bisogno, A Ligresti, E Morera…

Index: Ortar, Giorgio; Bisogno, Tiziana; Ligresti, Alessia; Morera, Enrico; Nalli, Marianna; Di Marzo, Vincenzo Journal of Medicinal Chemistry, 2008 , vol. 51, # 21 p. 6970 - 6979

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Citation Number: 71

Abstract

A series of 21 analogues of tetrahydrolipstatin (THL, 1) were synthesized and tested as inhibitors of the formation or hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2- AG). Three of the novel compounds, ie, 11, 13, and 15, inhibited 2-AG formation via the diacylglycerol lipase α (DAGLα) with IC50 values lower than 50 nM (IC50 of THL= 1 μM) and were between 23-and 375-fold selective vs 2-AG hydrolysis by monoacylglycerol lipase ( ...