(S)-1-(Pent-4′-enoyl)-4-(hydroxymethyl)-azetidin-2-one derivatives as inhibitors of human fatty acid amide hydrolase (hFAAH): synthesis, biological evaluation and molecular modelling

Figures & data

Figure 1. Representative inhibitors of hFAAH and hMAGL.

Figure 2. β-Lactone and β-lactam inhibitors of hMAGL and hFAAH, respectively.

Figure 3. General structures of studied hFAAH inhibitors and their respective precursors.

Scheme 1. Synthesis of 1,4-disubstituted β-lactams: (i) NaBH₄, MeOH, 0–20 °C, 3 h; (ii) carboxilic acid, DCC, DMAP (catal.), DCM, 20 °C, 24 h; (iii) acid chloride, pyridine or DMAP, DCM, 20 °C, 24 h; (iv) ClO-(CH₂)₂-CH=CH₂, pyridine, DCM, reflux, 24 h; (v) ClCO-(CH₂)₂-CH=CH₂, LiHMDS, THF-DMF, −78–20 °C, 1 h. See Table 1 for yields of 4 and 2.

Table 1. Yields of compounds (%) of the Scheme 1.

n	R*	4	Method	Yield (%)	2	Method	Yield (%)	Overall yield from B
3	Ph	4a	iii	72	2a	iv	43†	31
0	biPh	4b	iii	78	2b	v	65‡	51
1	biPh	4c	ii	87	2c	v	70	61
3	2-Pyr	4d	ii	79	2d	iv	17	13
3	4-Pyr	4e	ii	44	2e	iv	19	8
2	3-Ind	4f	ii	92	2f	iv	63	58
1	O-Bn	4g	ii	87	2g	v	66	57
2	O-Ph	4h	iii	75	2h	v	<5	<4

*  †Method v gave 40% yield.

‡Method iv gave 55% yield.

Figure 4. Intermediates resulting from the deprotonation of 4g and 4h, respectively.

Table 2. hFAAH and hMAGL inhibition.

			IC50/FAAH (µM)		IC50/MAGL (µM)
Compound	n	R*	Series 2	Series 1†	Series 2	Series 1†
a	3	Ph	5.03	0.005	108.10	4.06
b	0	biPh	0.91	nd	nd	nd
c	1	biPh	7.82	0.012	nd	1.84
d	3	2-Pyr	87.06	nd	nd	nd
e	3	4-Pyr	173.0	0.310	nd	nd
f	2	3-Ind	8.05	nd	166.10	nd
g	1	O-Bn	42.52	0.031	nd	nd

*See Table 1.

†Results of references 37 and 38.

Figure 5. Percentage of recovery of hFAAH activity after dilution with 2a versus controls.

Figure 6. Binding mode 1 of 1a and 2a in the active site of hFAAH. Hydrogens were removed for clarity.

Figure 7. Binding mode 2-1 W of 1a and 2a in the active site of hFAAH. Hydrogens were removed for clarity.

Figure 8. Binding mode 3-2 W of 1a and 2a in the active site of hFAAH. Hydrogens were removed for clarity.