title: 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, beta-picolylamine, 4-aminopyridine and piperazine was investigated; only two compounds (12) and (31) exhibited significant (approximately 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 x 100 microg/ear: 78 +/- 2%.
authors.affiliation: Laboratoire de Chimie Organique, UPRES EA 1155, Faculté de Pharmacie, 1 rue Gaston Veil, Université de Nantes, 44035 Nantes Cedex 01, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Breteche
authors.forename: Muriel
authors.initials: M
authors.lastname: Duflos
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dassonville
authors.forename: Marie-Renee
authors.initials: MR
authors.lastname: Nourrisson
authors.forename: Jacques
authors.initials: J
authors.lastname: Brelet
authors.forename: Guillaume
authors.initials: G
authors.lastname: Le Baut
authors.forename: Nicole
authors.initials: N
authors.lastname: Grimaud
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Petit
mesh_terms: D000284:Administration, Oral; D000287:Administration, Topical; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology*; D002351:Carrageenan / Q000633:toxicity; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
chemical_list: D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007211:Indoles; D002351:Carrageenan; D013755:Tetradecanoylphorbol Acetate