N-pyridinyl-indole-3-(alkyl)carboxamides and derivatives as potential systemic and topical inflammation inhibitors.
N-substituted-(indol-3-yl)carboxamides 10-15 and alkanamides 16-18 were prepared starting from the corresponding acids and submitted to screening for evaluation of their anti-inflammatory activity. None of the considered carboxamides exhibited significant inhibitory effect in the carrageenin-induced rat paw oedema after oral administration of 0.1 mM x kg(-1); nevertheless introduction of an alkyl chain, leading to alkanamides 16-18, induced moderate to high activity: 46-95% inhibition. The efficacy of these compounds in the inhibition of topical inflammation was confirmed by measuring reduction of ear thickness in the acute tetradecanoyl phorbol acetate (TPA)-induced mouse ear swelling assay. Preliminary pharmacomodulation brought to the fore that toxic effects induced, at 0.4 mM x kg(-1), by N-(pyridin-4-yl)(indol-3-yl)propanamide (17) could be attenuated or suppressed by 5-fluorination or introduction of a methoxycarbonylborane moiety, leading to 18 and 21.
Duflos
M
M
Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, 1 rue Gaston Veil, F-44035 Cedex, Nantes, France. muriel.duflos@sante.univ-nantes.fr
Nourrisson
M R
MR
Brelet
J
J
Courant
J
J
LeBaut
G
G
Grimaud
N
N
Petit
J Y
JY
D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D002351:Carrageenan / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004431:Ear, External / Q000187:drug effects / Q000473:pathology; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D007211:Indoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D011725:Pyridines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007211:Indoles; D011725:Pyridines; D002351:Carrageenan; D013755:Tetradecanoylphorbol Acetate