New N-pyridinyl(methyl)-N1-substituted-3-indolepropanamides acting as topical and systemic anti-inflammatory agents.
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 approximately 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 edema inhibition at 2 x 50 microg/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 aedema 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.
Gallard
Anthony
A
Laboratoires de Chimie Organique et de Chimie Thérapeutique, UPRES EA 1155, Faculté de Pharmacie, 1 rue Gaston Veil, F-44035 Nantes, France.
Duflos
Muriel
M
Nourrisson
Marie-Renee
MR
Le Baut
Guillaume
G
Grimaud
Nicole
N
Petit
Jean Yves
JY
D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002351:Carrageenan / Q000633:toxicity; D004431:Ear, External / Q000473:pathology; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005528:Foot / Q000473:pathology; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007211:Indoles; D011725:Pyridines; D002351:Carrageenan; D013755:Tetradecanoylphorbol Acetate