Structure–activity relationship studies of 3-dodecanoylindole-2-carboxylic acid inhibitors of cytosolic phospholipase A₂α-mediated arachidonic acid release in intact platelets: variation of the keto moiety

Figures & data

Figure 1 Structures of indole-2-carboxylic acid inhibitors of cPLA₂α-mediated arachidonic acid release in intact platelets.

Scheme 1 (i) SOCl₂, room temp.; (ii) dodecylmagnesium bromide, diethyl ether, THF, − 70°C; (iii) EtOH, 10% aqueous KOH, reflux; (iv) aqueous KMnO₄, acetone, room temp.; (v) dodecylamine, diethyl ether, 0°C/room temp.

Scheme 2 (i) Dodecanoyl chloride, CH₂Cl₂, triethylamine, pyridine, room temp.; (ii) methyl p-toluenesulfonate, (C₄H₉)₄N⁺Br⁻ , powdered NaOH, diethyl ether, CH₂Cl₂, room temp.; (iii) EtOH, 10% aqueous KOH, reflux.

Scheme 3 (i) Dodecan-1-ol, triphenylphosphine, THF, − 20°C; (ii) NaH, ethyl-4-(2-bromoethoxy)benzoate, DMF, room temp.; (iii) Pb(IV)acetate, acetic acid, room temp.; (iv) EtOH, 10% aqueous KOH, reflux.

Scheme 4 (i) tert-BuOK, ethyl 4-(2-bromoethoxy)benzoate, DMSO, 110°C; (ii) EtOH, 10% aqueous KOH, reflux.

Table I.  Inhibition of the cPLA₂α-mediated arachidonic acid release from human platelets stimulated with calcium ionophore A23187.

Compound	R	IC50 (μM)^a
1	COC11H23	4.8
9	SOC12H25	6.4
11	SO2C12H25	7.2
13	SONHC12H25	9.4
15	SO2NHC12H25	8.9
19	NHCOC11H23	6.3
20	CH2NHCOC11H23	10

^a Values are the means of at least two independent determinations; errors are within ± 20%; in case of 1: n = 6, standard deviation = ± 1.1 μM.

Table II.  Inhibition of cPLA₂α-activity.

			Cellular assay with intact human platelets	Vesicle assay with the isolated enzyme
Compound	R^1	R^2	IC50 (μM)^a	IC50 (μM)^a
4	COC11H23	H	0.86	n.a.^b
5	COC11H23	F	0.44	n.a.^b
25	SOC12H25	H	6.2	n.a.^b
26	SOC12H25	F	8.0	n.a.^b
27	NHCOC11H23	H	6.6	n.a.^b
28	NHCOC11H23	F	7.5	n.a.^b
AR-C70484XX^c			0.25	0.011

^a Values are the means of at least two independent determinations; errors are within ± 20%; in case of 4: n = 6, standard deviation = ± 0.1 μM.

^b n.a.: not active at 10 μM.

^c Reference compound 4-[3-(4-decyloxyphenoxy)-2-oxopropoxy]benzoic acid [23].

Connolly S, Bennion C, Botterell S, Croshaw PJ, Hallam C, Hardy K, Hartopp P, Jackson CG, King SJ, Lawrence L, Mete A, Murray D, Robinson DH, Smith GM, Stein L, Walters I, Wells E, Withnall WJ. J Med Chem 2002; 45: 1348–1362

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