Revisiting 1,3,4-Oxadiazol-2-ones: Utilization in the Development of ABHD6 Inhibitors

Bioorganic & Medicinal Chemistry
Jayendra Z PatelTapio Nevalainen

Abstract

This article describes our systematic approach to exploring the utility of the 1,3,4-oxadiazol-2-one scaffold in the development of ABHD6 inhibitors. Compound 3-(3-aminobenzyl)-5-methoxy-1,3,4-oxadiazol-2(3H)-one (JZP-169, 52) was identified as a potent inhibitor of hABHD6, with an IC₅₀ value of 216 nM. This compound at 10 μM concentration did not inhibit any other endocannabinoid hydrolases, such as FAAH, MAGL and ABHD12, or bind to the cannabinoid receptors (CB₁ and CB₂). Moreover, in competitive activity-based protein profiling (ABPP), compound 52 (JZP-169) at 10 μM selectively targeted ABHD6 of the serine hydrolases of mouse brain membrane proteome. Reversibility studies indicated that compound 52 inhibited hABHD6 in an irreversible manner. Finally, homology modelling and molecular docking studies were used to gain insights into the binding of compound 52 to the active site of hABHD6.

References

Nov 23, 2006·Biochemistry·Yassine Ben AliAbdelkarim Abousalham
Oct 16, 2008·Chembiochem : a European Journal of Chemical Biology·Giulio G MuccioliDidier M Lambert
Nov 1, 2012·Chemical Biology & Drug Design·Anna L Bowman, Alexandros Makriyannis
Dec 17, 2014·ChemMedChem·Jayendra Z PatelTeija Parkkari

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Citations

Jul 3, 2021·International Journal of Molecular Sciences·Agata ZiębaAgnieszka A Kaczor
Jul 3, 2021·Journal of Medicinal Chemistry·Giulia BononiCarlotta Granchi

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