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

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

  • Bioorg Med Chem. 2015 Oct 1;23(19):6335-45. doi: 10.1016/j.bmc.2015.08.030.
Jayendra Z Patel 1,  John van Bruchem 2,  Tuomo Laitinen 2,  Agnieszka A Kaczor 3,  Dina Navia-Paldanius 4,  Teija Parkkari 2,  Juha R Savinainen 4,  Jarmo T Laitinen 4,  Tapio J Nevalainen 2
Affiliations

Affiliations

  • 1 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland. Electronic address: [email protected].
  • 2 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
  • 3 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland; Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4a Chodzki St., PL-20093 Lublin, Poland.
  • 4 School of Medicine, Institute of Biomedicine/Physiology, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
PMID: 26344596 DOI: 10.1016/j.bmc.2015.08.030
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.

Keywords

1,3,4-Oxadiazol-2-ones; 2-Arachidonoylglycerol; Fatty acid amide hydrolase; Monoacylglycerol lipase; α/β-Hydrolase domain-containing 6.

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