Structure–activity relationship studies on 1-heteroaryl-3-phenoxypropan-2-ones acting as inhibitors of cytosolic phospholipase A₂α and fatty acid amide hydrolase: replacement of the activated ketone group by other serine traps

Figures & data

Figure 1. Heteroaryl-substituted propan-2-ones with preferential inhibition of cPLA₂α (1 and 2) and FAAH (3–6).

Scheme 1. Reagents and conditions: (a) Ethyl bromoacetate, Cs₂CO₃, KI, acetonitrile, room temperature, 16 h; (b) diisobutylaluminium hydride, cyclohexane, THF, −70 °C to room temperature, 4 h; (c) acetone cyanhydrin, triethylamine, CH₂Cl₂, room temperature, 4 h; (d) 1. acetyl chloride, ethanol, chloroform, 0 °C, 1 h; 2. 2–amino-4-phenoxyphenol, ethanol, reflux, 6 h; (e) Dess-Martin periodinane, CH₂Cl₂, room temperature, 4 h; (f) tetrakis(triphenylphosphine)palladium(0), acetic acid, THF, room temperature.

Scheme 2. Reagents and conditions: (a) Bromoacetaldehyde diethyl acetal, DMF, NaHCO₃, reflux, 18 h; (b) conc. HCl, THF, room temperature, 5 h; (c) acetone cyanhydrin, triethylamine, CH₂Cl₂, room temperature, 5 h; (d) 1. acetyl chloride, ethanol, chloroform, 0 °C, 1 h; 2. 2–amino-4-phenoxyphenol, ethanol, reflux, 6 h; (e) Dess-Martin periodinane, CH₂Cl₂, room temperature, 4 h.

Scheme 3. Reagents and conditions: (a) 4-Phenoxyphenol, NaH, DMF, 70 °C, 3 h; (b) p-toluenesulfonic acid, methanol, room temperature, 4 h; (c) tosyl chloride, 4-dimethylaminopyridine, triethylamine, CH₂Cl₂, room temperature, 12 h; (d) allyl indole-5-carboxylate, NaH, DMF, 80 °C, 3 h; (e) trifluoroacetic acid, CH₂Cl₂, room temperature, 2 h; (f) cyanogen bromide, CH₂Cl₂, NaHCO₃, THF, 0 °C, 2 h; (g) tetrakis(triphenylphosphine)palladium(0), acetic acid, THF, room temperature.

Scheme 4. Reagents and conditions: (a) Cyanogen bromide, CH₂Cl₂, NaHCO₃, diethyl ether, 0 °C, 2 h.

Scheme 5. Reagents and conditions: (a) 4-Phenoxyphenol, NaH, DMF, 80 °C, 3 h; (b) 5 M HCl, methanol, room temperature, overnight; (c) p-toluenesulfonyl chloride, 4-dimethylaminopyridine, triethylamine, THF, room temperature, 12 h; (d) tert–butyldimethylsilyl chloride, CH₂Cl₂, triethylamine, room temperature, 4 h; (e) allyl indole-5-carboxylate, NaH, DMF, 70 °C, 3 h; (f) tetrabutylammonium fluoride, THF, room temperature, 1 h; (g) 1. Dess-Martin periodinane, acetic acid, CH₂Cl₂, room temperature, 1.5 h; 2. hydroxylammonium chloride, pyridine, room temperature, overnight; (h) 2-chloro-1-methylpyridinium iodide, THF, triethylamine, room temperature, 20 h; (i) tetrakis(triphenylphosphine)palladium(0), acetic acid, THF, room temperature.

Scheme 6. Reagents and conditions: (a) Tetrazole, acetonitrile, DMF, NaOH, 100 °C, 2 h; (b) tetrabutylammonium fluoride, THF, room temperature, 2 h; (c) 1. Dess-Martin periodinane, acetic acid, CH₂Cl₂, room temperature, 1.5 h; 2. hydroxylammonium chloride, pyridine, room temperature, overnight; (d) 2-chlor-1-methylpyridinium iodide, THF, triethylamine, room temperature, 20 h.

Table 1. cPLA₂α inhibitory potency and metabolic stability in rat liver S9 fractions of (5-carboxyindol-1-yl)propan-2-ones.

Comp.	R	Inhibition of cPLA2α IC50 (µM)*	Metabolic stability (%)¶
2	=O	0.021	0
13		1.6	0
27	NHCN	>10†	14
39	CN	n.a. ‡	74

*Values are the means of at least two independent determinations, errors of the IC₅₀ values are within ± 20%; inhibition value of reference inhibitor Axon 160930 (CAS 479422-22-5): IC₅₀ = 0.21 µM.

†32% inhibition at 10 µM.

‡Not active at 10 µM.

¶Percentage of parent compound remaining after metabolism by rat liver microsomes in presence of NADPH; values are the means of at least two independent determinations. Metabolic stability of reference inhibitor 3-(5-carboxypentanoyl)-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid12 (CAS 1138028-71-3): 63 ± 6.7 % (n = 9).

Table 2. FAAH inhibitory potency and metabolic stability in rat liver S9 fractions of (1H-benzotriazol-1-yl)- and (2H-tetrazol-2-yl)propan-2-ones.

Comp.	R	Inhibition of FAAH IC50 (µM)*	Metabolic stability (%)‡
4		0.024	0
19		10	0
6	=O	0.008	0
29	NHCN	5.3	25
43	CN	n.a.†	57

*Values are the means of at least two independent determinations, errors of the IC₅₀ values are within ± 20%; inhibition value of reference inhibitor URB59731 (CAS 546141-08-6): IC₅₀ = 0.060 µM.

†Not active at 10 µM.

‡Percentage of parent compound remaining after metabolism by rat liver microsomes in presence of NADPH; values are the means of at least two independent determinations. Metabolic stability of reference inhibitor 3-(5-carboxypentanoyl)-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid12: 63 ± 6.7 % (n = 9).

McKew JC, Foley MA, Thakker P, et al. Inhibition of cytosolic phospholipase A2α: hit to lead optimization. J Med Chem 2006;49:135–58

 PubMed Web of Science ®Google Scholar

Bovens S, Schulze Elfringhoff A, et al. 1-(5-Carboxyindol-1-yl)propan-2-one inhibitors of human cytosolic phospholipase A2α: effect of substituents in position 3 of the indole scaffold on inhibitory potency, metabolic stability, solubility, and bioavailability. J Med Chem 2010;53:8298–308

 PubMed Web of Science ®Google Scholar

Kathuria S, Gaetani S, Fegley D, et al. Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med 2003;9:76–81

 PubMed Web of Science ®Google Scholar