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Canna~Fangled Abstracts

1,3,4-Oxadiazol-2-ones as fatty-acid amide hydrolase and monoacylglycerol lipase inhibitors: Synthesis, in vitro evaluation and insight into potency and selectivity determinants by molecular modelling.

By April 18, 2013No Comments

Pub Med

1,3,4-Oxadiazol-2-ones as fatty-acid amide hydrolase and monoacylglycerol lipase inhibitors: Synthesis, in vitro evaluation and insight into potency and selectivity determinants by molecular modelling.

Käsnänen H, Minkkilä A, Taupila S, Patel JZ, Parkkari T, Lahtela-Kakkonen M, Saario SM, Nevalainen T, Poso A.

Source

School of Pharmacy, University of Eastern Finland, P.O.Box 1627, FI-70211 Kuopio, Finland.

Abstract

Inhibition of the key hydrolytic enzymes of the endocannabinoid system, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), has been proposed as potential mode of action for various therapeutic applications. Continuing our previous work, we take the first steps of structure-activity relationship exploration and show that 1,3,4-oxadiazol-2-ones can serve as scaffold for both selective FAAH and MAGL inhibitors, and also function as a dual FAAH/MAGL inhibitor at sub-micromolar IC50 values. Moreover, 10-fold selectivity against MAGL over FAAH was achieved with compound 3d (FAAH and MAGL IC50; 2.0 and 0.22 μM). Lastly, enzyme and ligand features contributing to the potency and selectivity differences are analysed by molecular docking.

Copyright © 2013. Published by Elsevier B.V.

PMID:

23557840
 
[PubMed – as supplied by publisher] prisoner of the system2
http://www.ncbi.nlm.nih.gov/pubmed/23557840