| Autor: |
Breteche, Anne, Duflos, Muriel, Dassonville, Alexandra, Nourrisson, Marie-Renee, Brelet, Jacques, Le Baut, Guillaume, Grimaud, Nicole, Petti, Jean-Yves |
| Předmět: |
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| Zdroj: |
Journal of Enzyme Inhibition & Medicinal Chemistry; Dec2002, Vol. 17 Issue 6, p415-424, 10p, 6 Diagrams, 4 Charts |
| Abstrakt: |
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: ID 50 =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%. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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