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Screening Of Various Hormone‐Sensitive Lipase Inhibitors As Endocannabinoid‐Hydrolyzing Enzyme Inhibitors

Anna Minkkilae, Juha R. Savinainen, Heikki Käsnänen, Henri Xhaard, T. Nevalainen, Jarmo T. Laitinen, A. Poso, J. Leppänen, Susanna M. Saario
Published 2009 · Chemistry, Medicine

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Three classes of chemically diverse hormone-sensitive lipase (HSL) inhibitors, including oxadiazolones, 2H-isoxazol-5-ones and carbamoyl triazoles, were evaluated for their ability to inhibit endocannabinoid-hydrolyzing enzymes, fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL, also called monoacylglycerol lipase (MAGL)). All the compounds belonging to these compound classes inhibited both FAAH and MGL with IC50 values varying from the nanomolar to low micromolar range. The most potent FAAH inhibitor was 2H-isoxazol-5-one 10 c with an IC50 value of 0.45 nm, whereas the most promising MGL inhibitor, albeit not selective over FAAH, was 1,3,4-oxadiACHTUNGTRENNUNGazol-2(3H)-one 16 c (IC50 = 78 nm against 2-AG hydrolysis). These results suggest that HSL inhibitors investigated in this paper may provide useful leads for the development of novel FAAH and/or MGL inhibitors. N-arachidonoylethanolamine (anandamide, AEA) and 2arachidonoylglycerol (2-AG) are the two best known and most investigated endocannabinoids that activate cannabinoid CB1 [3] and CB2 [4] receptors and modulate several physiological processes, such as pain sensation and inflammation (for reviews, see Reference [5]). However, endogenous levels of AEA and 2-AG are normally low, as these endocannabinoids are rapidly degraded by the specific enzymes, FAAH (EC 3.5.1.4) and MGL (EC 3.1.1.23), respectively. Inactivation of FAAH and MGL by chemical inhibitors leads to elevated levels of AEA and 2-AG, which have been evidenced to be an attractive and valuable goal in the treatment of a variety of pathological conditions. 8] In recent years, a range of different classes of FAAH inhibitors have been developed, mainly derivatized from the other known serine hydrolase inhibitors (for a review, see Reference [9]). These include various substrate analogues, as well as nonlipid inhibitors such as a-keto heterocycles, carbamates, (thio)hydantoins, piperidine/piperazine ureas and most recently, benzothiazole-based sulfonyl derivatives and boronic acids. Within carbamate-based inhibitors, cyclohexylcarbamic acid biphenyl-3-yl ester (URB597) (1) has been shown to be effica-
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