4-Aryliden-2-methyloxazol-5(4H)-one as a new scaffold for selective reversible MAGL inhibitors

Figures & data

Figure 1. Structures of some of the most relevant MAGL inhibitors.

Figure 2. Design of the methyleneoxazol-5(4H)-one scaffold (II).

Scheme 1. Reagents and conditions: (a) N-acetylglycine, Ac₂O, CH₃COONa, reflux, 5 h.

Scheme 2. Reagents and conditions: (a) N-acetylglycine, Ac₂O, CH₃COONa, reflux, 5 h.

Scheme 3. Reagents and conditions: (a) appropriately substituted phenylboronic acid, Pd(OAc)₂, PPh₃, aq. 2 M Na₂CO₃, toluene, EtOH, 100 °C, 24 h and (b) N-acetylglycine, Ac₂O, CH₃COONa, reflux, 5 h.

Scheme 4. Reagents and conditions: (a) NaOH 1 N, 90 °C, then HCl 3 N, 0 °C.

Table 1. Experimental inhibition activity (IC₅₀) on human MAGL and FAAH of the analyzed compounds.

#	MAGL IC50 (µM)	FAAH IC50 (µM)	Selectivity
2	24.1 ± 0.2	>200	>20
3	116 ± 7	>200	>2
4	>200	>200	–
16a	2.1 ± 0.3	94.0 ± 3.7	45
16b	1.6 ± 0.2	111 ± 7	69
16c	2.2 ± 0.2	33.9 ± 0.0	15
17a	1.2 ± 0.1	52.3 ± 3.6	44
17b	1.1 ± 0.1	69.1 ± 5.3	63
17c	1.0 ± 0.1	48.9 ± 0.8	49
18a	1.1 ± 0.1	45.4 ± 2.0	41
18b	1.7 ± 0.1	67.3 ± 2.8	40
18c	1.3 ± 0.1	37.3 ± 6.8	29
19	>200	>200	–
CAY10499	0.144 ± 0.003	0.014 ± 0.001	0.1
JZL-184	0.049 ± 0.004	3.3 ± 0.2	67

Figure 3. Compound 16b-hMAGL inhibition analysis. (A) Effect of DTT on the hMAGL inhibition properties. (B) Dilution assay: the first two columns indicate the inhibition percentage of compound 16b at a concentration of 40 and 1 µM. The third column indicates the inhibition percentage of compound 16b after dilution (final concentration = 1 µM). (C) IC₅₀ (µM) values of 16b at different preincubation times with hMAGL (0, 30 and 60 min).

Table 2. Cell growth inhibitory activities (IC₅₀) of compounds.

	IC50 (µM)
#	MCF-7	MB-231	COV318	OVCAR-3
16b	18.1 ± 2.8	42.1 ± 4.2	42.1 ± 5.1	10.0 ± 1.9
17b	15.8 ± 2.3	38.1 ± 4.2	50.5 ± 6.1	28.8 ± 3.5
18b	23.7 ± 1.8	54.4 ± 4.8	50.2 ± 5.1	18.0 ± 3.2
JZL-184	26.0 ± 5.1	37.8 ± 5.0	56.6 ± 3.2	52.9 ± 5.7
CAY10499*	4.2 ± 1.2	46.0 ± 6.9	106.7 ± 21.5	79.8 ± 11.7

*Ref. 23.

Figure 4. Docking of 16b (A), 17b (B), 18b (C) and CAY10499 (D) into the human MAGL receptor.

Figure 5. Docking of CAY10499 (A), 16b (B), 17b (C) and 18b (D) into humanized-rat FAAH receptor.