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

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%.

Keywords::

• Amino(methyl)pyridines
• Non Acidic And Non Steroidal Anti-inflammatory Drugs
• (Derivatives Of) 2 And 3-indol(alkyl)carboxamides
• 3-indazolcarboxamides