Revisiting 1,3,4-Oxadiazol-2-ones: Utilization in the Development of ABHD6 Inhibitors.
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.
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland. Electronic address: jayendra.patel@uef.fi.
Jayendra Z
JZ
Patel
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
John
J
van Bruchem
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
Tuomo
T
Laitinen
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.
Agnieszka A
AA
Kaczor
School of Medicine, Institute of Biomedicine/Physiology, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
Dina
D
Navia-Paldanius
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
Teija
T
Parkkari
School of Medicine, Institute of Biomedicine/Physiology, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
Juha R
JR
Savinainen
School of Medicine, Institute of Biomedicine/Physiology, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
Jarmo T
JT
Laitinen
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
Tapio J
TJ
Nevalainen
D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D062105:Molecular Docking Simulation; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010069:Oxadiazoles / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D043882:Receptors, Cannabinoid / Q000737:chemistry / Q000378:metabolism; D057057:Serine Proteases / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
C586624:1,3,4-oxadiazol-2(3H)-one; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D043882:Receptors, Cannabinoid; C527261:ABHD6 protein, mouse; D008994:Monoacylglycerol Lipases; D057057:Serine Proteases
1,3,4-Oxadiazol-2-ones; 2-Arachidonoylglycerol; Fatty acid amide hydrolase; Monoacylglycerol lipase; α/β-Hydrolase domain-containing 6