Structure-Activity Relationship of a New Series of Reversible Dual Monoacylglycerol Lipase / Fatty Acid Amide Hydrolase Inhibitors.

Structure-Activity Relationship of a New Series of Reversible Dual Monoacylglycerol Lipase / Fatty Acid Amide Hydrolase Inhibitors.

J Med Chem. 2011 Dec 21;

Authors: Cisneros JA, Björklund E, González-Gil I, Hu Y, Canales A, Medrano FJ, Romero A, Ortega-Gutierrez S, Fowler CJ, Lopez-Rodrí Guez ML

Abstract

The two endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG) play independent and non-redundant roles in the body. This makes the development of both selective and dual inhibitors of their inactivation an important priority. In this work we report a new series of inhibitors of monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). Among them, (±)-oxiran-2-ylmethyl 6-(1,1′-biphenyl-4-yl)hexanoate (8) and (2R)-(-)-oxiran-2-ylmethyl(4-benzylphenyl)acetate (30) stand out as potent inhibitors of human recombinant MAGL (IC50 (8) = 4.1 μM; IC50 (30) = 2.4 μM), rat brain monoacylglycerol hydrolysis (IC50 (8) = 1.8 μM; IC50 (30) = 0.68 μM) and rat brain FAAH (IC50 (8) = 5.1 μM; IC50 (30) = 0.29 μM). Importantly, and in contrast to the other previously described MAGL inhibitors, these compounds behave as reversible inhibitors either of competitive (8) or non-competitive nature (30). Hence, they could be useful to explore the therapeutic potential of reversible MAGL inhibitors.

PMID: 22185522 [PubMed - as supplied by publisher]