Development of terphenyl-2-methyloxazol-5(4H)-one derivatives as selective reversible MAGL inhibitors

Abstract

Monoacylglycerol lipase is a serine hydrolase that plays a major role in the degradation of the endocannabinoid neurotransmitter 2-arachidonoylglycerol. A wide number of MAGL inhibitors are reported in literature; however, many of them are characterised by an irreversible mechanism of action and this behavior determines an unwanted chronic MAGL inactivation, which acquires a functional antagonism of the endocannabinoid system. The possible use of reversible MAGL inhibitors has only recently been explored, due to the lack of known compounds possessing efficient reversible inhibitory activities. In this work, we report a new series of terphenyl-2-methyloxazol-5(4H)-one derivatives characterised by a reversible MAGL-inhibition mechanism. Among them, compound 20b showed to be a potent MAGL reversible inhibitor (IC₅₀ = 348 nM) with a good MAGL/FAAH selectivity. Furthermore, this compound showed antiproliferative activities against two different cancer cell lines that overexpress MAGL.

Keywords: Monoacylglycerol lipase inhibitors; docking; endocannabinoids; molecular dynamic simulations.

Figure 1.

Structures of some of the most relevant MAGL inhibitors.

Figure 2.

Structural evolution of methyleneoxazol-5(4H)-one scaffold: previously developed biphenyl 2-methyloxazol-5(4H)-one compounds (A) and newly synthesised terphenyl-2-methyloxazol-5(4H)-one derivatives (B).

Scheme 1.

Reagents and conditions: (a) for compound 4: phenylboronic acid, Pd(OAc)₂, K₃PO₄, TBAB, H₂O, 125 °C; for compound 6: phenylboronic acid, Pd(OAc)₂, PPh₃, aq. 2 M Na₂CO₃, toluene, EtOH, 100 °C; for compound 8: phenylboronic acid, Pd(OAc)₂, PPh₃, aq. 2 M Na₂CO₃, toluene, EtOH, 100 °C, then phenylboronic acid, Pd₂(dba)₃, Cs₂CO₃, Cy₃P 20% toluene, dioxane, 100 °C; (b) N-acetylglycine, Ac₂O, CH₃COONa, reflux.

Scheme 2.

Reagents and conditions: (a) phenylboronic acid, Pd(OAc)₂, PPh₃, aq. 2 M Na₂CO₃, toluene, EtOH, 100 °C; (b) N-acetylglycine, Ac₂O, CH₃COONa, reflux.

Scheme 3.

Reagents and conditions: (a) phenylboronic acid, Pd₂(dba)₃, Cs₂CO₃, Cy₃P 20% toluene, dioxane, 100 °C; b) N-acetylglycine, Ac₂O, CH₃COONa, reflux.

Scheme 4.

Reagents and conditions: (a) variously substituted phenylboronic acid, Pd(OAc)₂, PPh₃, aq. 2 M Na₂CO₃, toluene, EtOH, 100 °C; (b) N-acetylglycine, Ac₂O, CH₃COONa, reflux.

Figure 3.

Compound 20b-MAGL inhibition analysis. (A) IC₅₀ (µM) values of 20b at different preincubation times with hMAGL (0, 30 and 60 min). (B) Dilution assay: the first two columns indicate the inhibition percentage of compound 20b at a concentration of 10 and 0.25 µM. The third column indicates the inhibition percentage of compound 20b after dilution (final concentration = 0.25 µM).

Figure 4.

Minimised average structure of compound 20b docked into MAGL receptor (A) and analysis of 20b-MAGL H-bond interactions (B). The plot shows the distance analysis for the two H-bonds (i.e. HB1 and HB2).

Figure 5.

Minimised average structure of compound 20b docked into FAAH receptor.