New N-Pyridinyl(methyl)-N1-substituted-3-indolepropanamides Acting as Topical and Systemic Anti-inflammatory Agents

Abstract

N-Pyridinyl(methyl)-N1-substituted-3-indolepropanamides (17–32) were prepared starting from the corresponding acids and screened for their anti-inflammatory activity. Pharmacomodulation was carried out on the indole and amidic nitrogens by incorporation of substituents associated with higher potency in previously synthesized related 3-indolepropanamides series. In the inhibition of topical inflammation determined by reduction of ear thickness in the acute PMA mouse ear swelling test, high levels of activity (ID50∼0.030 mMol kg-1) were noticed for the five propanamides 17, 21, 22, 27 and 31. A comparative study showed the positive influence of a methyl group at the indole nitrogen in the 4-pyridinyl sub-series (1→21) and of a 4-fluorobenzyl group in the 3-pyridinylmethyl sub-series (19→31), at least after oral administration. After topical application, although compounds 17, 21, 22, 27 and 31 exerted significant (50%) ear œdema inhibition at 2×50 μg/ear, they remained less potent than 24, 29 and 30 (almost 70% inhibition). Among these eight amides, only 17, 21, 22 and 27 showed a significant activity in the carrageenan rat paw œdema model at 0.2 mMol kg-1. Finally, although less active than the N-(4-pyridinyl) amide 21, the N-4,6-dimethyl-2-pyridinyl derivatives 17 and 27 were devoid of the toxic effects observed with 21 and to a lesser extent with 22.

Keywords: :

• -pyridinyl and -pyridinylmethyl-3-indolepropanamides
• Topical and systemic inflammation inhibitors