Design and synthesis of 3-pyrrol-3-yl-3H-isobenzofuran-1-ones as inhibitors of human cytosolic phospholipase A₂α

Figures & data

Figure 1.  Structures of known cPLA₂α inhibitors.

Scheme 1 (a) Hydroxylamine-HCl, Na₂CO₃, methanol, reflux; (b) TiCl₄, NaBH₄, 1,2-dimethoxyethane, room temp.; (c) ethyl trifluoroacetate, THF, 0°C; (d) 7, SnCl₄, 1,2-dichlororethane, reflux; (e) KOH, water, methanol, room temperature; (f) 4-(2,4-dioxothiazolidin-5-ylidenemethyl)benzoic acid, EDC, 1-hydroxybenzotriazole, DMF, room temp.

Scheme 2 (a) 11: 7, SnCl₄, 1,2-dichlororethane, 50°C; 12: 2-acetylbenzoic acid, 120–140°C; 13: 2-formylbenzoic acid, toluene, reflux.

Scheme 3 (a) 14: 7, AlCl₃, 1,2-dichlororethane, room temp.; 15: 7, SnCl₄, 1,2-dichlororethane, 50°C.

Scheme 4 (a) p-Toluenesulfonic acid, toluene, reflux; (b) 7, SnCl₄, 1,2-dichlororethane, 50°C.

Table I.  Inhibition of cPLA₂α-activity

	Vesicle assay with the isolated enzyme	Cellular assay with intact human platelets
Compound	IC50 (μM)^a	IC50 (μM)^a
10	26	3.1
11	>33^b	8.0
1 (AACOCF3)	2.3	3.3

^aValues are the means of at least two independent determinations; errors are within ± 20%. ^bInhibition of enzyme activity: 40% at 33 μM.

Table II.  Inhibition of cPLA₂α-activity

			Vesicle assay with the isolated enzyme
Compound	R^1	R^2	Inhibition at 33 μM (%)^a
11	4-F-phenyl	Phenyl	40
12	CH3	Phenyl	n.a.^b
13	H	Phenyl	n.a.^b
14	4-F-phenyl	CH3	36
15	4-F-phenyl	H	35
16	4-F-phenyl	Benzyl	18
17	4-F-phenyl	Benzhydryl	n.a.^b

^aValues are the means of at least two independent determinations. ^bn.a.: not active at 33 μM.

Table III.  inhibition Of Cpla₂α-activity

		Vesicle assay with the isolated enzyme
Compound	R	Inhibition at 33 μM (%)^a
11	Phenyl	40
18	4-phenylphenyl	n.a.
19	4-Cl-phenyl	n.a.
20	4-CH3-phenyl	n.a.
21	4-OCH3-phenyl	n.a.
22	4-CN-phenyl	n.a.
24	4-COOH-phenyl	51
25	4-CONH2-phenyl	42
26	4-NHCOCH3-phenyl	35
27	4-NH2-phenyl	55
29	4-NHCH3-phenyl	36
30	4-N(CH3)2-phenyl	n.a.
31	4-OH-phenyl	60
32	3-OH-phenyl	30
34	3,4-diOH-phenyl	20
35	2,4-dioxothiazolidin-5-ylidenemethyl	76

^aValues are the means of at least two independent determinations. ^bn.a.: not active at 33 μM.

Figure 2.  Structure of 35.

Table IV.  Inhibition of cPLA₂α-activity

		Vesicle assay with the isolated enzyme	Cellular assay with intact human platelets
Compound	R	IC50 (μM)^a	IC50 (μM)^a
11	Phenyl	>33^b	8.0
27	4-NH2-phenyl	27	2.8
31	4-OH-phenyl	22	2.8
32	3-OH-phenyl	>33^c	2.0
34	3,4-diOH-phenyl	>33^d	1.3
35	2,4-dioxothiazolidin-5-ylidenemethyl	7.3	0.7

^aValues are the means of at least two independent determinations; errors are within ± 20%. ^bInhibition of enzyme activity: 40% at 33 μM. ^cInhibition of enzyme activity: 30% at 33 μM. ^dInhibition of enzyme activity: 20% at 33 μM.