1-(5-Carboxyindazol-1-yl)propan-2-ones as dual inhibitors of cytosolic phospholipase A₂α and fatty acid amide hydrolase: bioisosteric replacement of the carboxylic acid moiety

Figures & data

Figure 1. Indole- and indazole-5-carboxylic acid inhibitors of cPLA₂α and/or FAAH.

Scheme 1. Reagents and conditions: (a) 4-Phenoxyphenol, 4-(dimethylamino)pyridine, 120 °C, 45 min; (b) Dess-Martin periodinane, CH₂Cl₂, room temp., 2.5 h; (c) 10% aqueous KOH, ethanol, room temp., 14 h.

Scheme 2. Reagents and conditions: (a) Cs₂CO₃, DMF, room temp., 23 h; (b) Dess-Martin periodinane, CH₂Cl₂, room temp., 3 h.

Scheme 3. Reagents and conditions: (a) 15: Acetic anhydride, THF, triethylamine, room temp., 1.5 h; 18: isobutyryl chloride, pyridine, 0 °C, 2 h; 22: di-tert-butyl dicarbonate, methanol, Amberlyst® 15, room temp., 2 h; 26: 2-methoxyacetyl chloride, pyridine, 0 °C, 2 h; 30: 2-benzyloxyacetyl chloride, diisopropyl(ethyl)amine, DMF, 0 °C to room temp., 4 h; 34: methyl chloroformate, pyridine, 0 °C, 2 h; (b) 15: epichlorohydrin, Cs₂CO₃, acetonitrile, reflux, 3 h; 19, 23, 27, 31, 35: epichlorohydrin, Cs₂CO₃, DMF, room temp., 16–24 h; (c) 4-phenoxyphenol, 16, 32: Cs₂CO₃, tetrabutylammonium bromide, acetonitrile, reflux, 4–7 h; 20: 4-(dimethylamino)pyridine, DABCO, DMF, 120 °C, 1 h; 24: DABCO, DMF, 120 °C, 6 h; 28: DABCO, 4-(dimethylamino)pyridine, DMF, 120 °C, 4 h, 36: 4-(dimethylamino)-pyridine, 120 °C, 2 h; (d) 17, 21, 29, 37: acetic anhydride, DMSO, room temp., 12–16 h, 25: Dess-Martin periodinane, CH₂Cl₂, room temp., 4.5 h followed by trifluoroacetic acid, CH₂Cl₂, room temp., 18 h, 33: Dess-Martin periodinane, CH₂Cl₂, room temp., 3 h; (e) benzoyl chloride, ethyl acetate, pyridine, room temp., 2 h; (f) H₂, Pd/C, THF, room temp., 4 d.

Scheme 4. Reagents and conditions: (a) 2-[(4-Phenoxyphenoxy)methyl]oxirane, Cs₂CO₃, DMF, room temp., 72 h; (b) tert-butyldimethylsilyl chloride, imidazole, THF, room temp., 2 d; (c) H₂, Pd/C, THF, 5 h; (d) 44: phenyl chloroformate, THF, room temp., 1 h; 47: phenyl isocyanate, THF, room temp., 30 min; (e) CuCl₂ dihydrate, acetone, H₂O, reflux, 40 h (45) or 8 h (48); (f) Dess-Martin periodinane, CH₂Cl₂, room temp., 1.5 h (48) or 4 h (49).

Scheme 5. Reagents and conditions: (a) Dess-Martin periodinane, CH₂Cl₂, room temp., 4 h; (b) triethyl orthoformate, H₂SO₄ conc., ethanol, reflux, 12 h; (c) H₂, Pd/C, THF, 5.5 h; (d) 53: ethyl isocyanate, THF, room temp., 1 d, 55: cyclohexyl isocyanate, THF, room temp., 6 d; (e) 54: H₂O, acetone, water, H₂SO₄ conc., room temp., 2 d, 56: ethanol, acetone, THF, water, H₂SO₄ conc., room temp., 4 d.

Scheme 6. Reagents and conditions: (a) Methanesulfonamide (57), benzenesulfonamide (58) or trifluoromethanesulfonamide (59), 4-(dimethylamino)pyridine, CH₂Cl₂, EDC, room temp., 20–42 h.

Table 1. Inhibition of cPLA₂α and FAAH.

Comp.	R	Inhibition of cPLA2α IC50 (μM)*	Inhibition of FAAH IC50 (μM)*
8	COOH	0.005	0.055
12	H	6.3	2.6
17	NHCOCH3	0.13	3.9
21	NHCOCH(CH3)2	n.a.	>10^¶
38	NHCOPhenyl	n.a.	>10^‡
29	NHCOCH2OCH3	0.59	6.3
39	NHCOCH2OH	0.66	5.4
33	NHCOCH2OCH2Phenyl	2.3	>10^§
37	NHCOOCH3	2.1	4.0
46	NHCOOPhenyl	>10†	2.1
50	NO2	0.55	0.55
54	NHCONHC2H5	n.a.	1.6
56	NHCONHCyclohexyl	n.a.	0.84
49	NHCONHPhenyl	n.a.	6.0
57	CONHSO2CH3	1.6	0.77
58	CONHSO2Phenyl	1.9	4.7
59	CONHSO2CF3	0.29	0.51

*Values are the means of at least two independent determinations, errors of the IC₅₀ values are within ± 20%; inhibition value of cPLA₂α reference inhibitor Axon 160921 (CAS 479422–22-5): IC₅₀=0.21 μM; inhibition value of FAAH reference inhibitor URB59722 (CAS 546141-08-6): IC₅₀=0.060 μM.

† 44% inhibition at 10 μM.

‡ 44% inhibition at 10 μM.

¶ 26% inhibition at 10 μM.

§ 37% inhibition at 10 μM.

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