New N -pyridinyl(methyl)-indole-2- and 3-(Alkyl)carboxamides and Derivatives Acting as Systemic and Topical Inflammation Inhibitors |
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Authors: | Anne Breteche Muriel Duflos Alexandra Dassonville Marie-Renee Nourrisson Jacques Brelet Guillaume Le Baut |
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Institution: | Laboratoires de Chimie Organique et de Chimie Thérapeutique, UPRES EA 1155, Faculté de Pharmacie, 1 rue Gaston Veil, Université de Nantes, 44035 Nantes Cedex 01- France |
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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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Keywords: | Amino(methyl)pyridines Non Acidic And Non Steroidal Anti-inflammatory Drugs (Derivatives Of) 2 And 3-indol(alkyl)carboxamides 3-indazolcarboxamides |
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