New N-pyridinyl(methyl)-indole-2- and 3-(Alkyl)carboxamides and Derivatives Acting as Systemic and Topical Inflammation Inhibitors

Author： Breteche Anne   Duflos Muriel   Dassonville Alexandra   Nourrisson Marie-Renee   Brelet Jacques   Le Baut Guillaume   Grimaud Nicole   Petit Jean-Yves  

Publisher： Informa Healthcare

ISSN： 1475-6366

Source： Journal of Enzyme Inhibition and Medicinal Chemistry, Vol.17, Iss.6, 2002-01, pp. : 415-424

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Abstract

A series of novel N-substituted-(indol-2-yl)carboxamides (12-18) and (indol-3-alkyl)carboxamides (25-31) were synthesized and evaluated as inhibitors of the inflammation process. Pharmacomodulation at the level of the amidic nitrogen by incorporation of the previously described pharmacophoric moieties 6-aminolutidine, β-picolylamine, 4-aminopyridine and piperazine was investigated; only two compounds (12) and (31) exhibited significant (∼40%) inhibitory effect in the carrageenan-induced rat paw edema after oral administration of a dose of 0.1 mM kg−1. Replacement of the indole core by indazole failed to increase activity. Incorporation of an alkyl chain spacer led to more efficient compounds (46-52) especially in the indolepropanamide sub-series. Determination of the efficiency of the most active compounds on topical inflammation, by measuring reduction of ear thickness in the acute tetradecanoyl phorbol acetate (TPA)-induced mouse ear swelling assay, confirmed the high potency of propanamides (49) and (51) after oral administration: ID50=0.041±0.013 and 0.042±0.016 mM kg−1 respectively. The less toxic propanamide (51) exerted a high level of inhibitory activity after topical application of 2 × 100 μg/ear: 78±2%.

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