6-AMINO-2,4-LUTIDINE CARBOXAMIDES - ALPHA-AMINOAMIDE DERIVATIVES AS SYSTEMIC AND TOPICAL INFLAMMATION INHIBITORS

The development of new potential anti-inflammatory compounds resulting from the incorporation of alpha-aminoacid residues into 6-amino-2,3-l utidine afforded (N-protected) aminoamides with interesting inhibitory activity. Out of 28 tested compounds, 10 (5a, 5b, 7d, 8a, 8b, 8d, 10a , 11b, 12a and 12b) exerted potent (> 90%) inhibition in the carrageen an foot edema (CFE) rat model after oral administration of 0.4 mmol kg (-1). Except for Cbz-glycyl, Cbz-alanyl, Fmoc-valyl and Cbz-alanyl-gly cyl derivatives (5a, 5b, 7d and 11b), N-deprotection afforded more act ive compounds. Introduction of a glycyl residue in the previously stud ied highly active 3-fluorobenzamide 2, which led to 10a, maintained po tent peripheral edema inhibition but had a detrimental effect in the a cute TPA-induced mouse ear-swelling model. Glycylglycinamide 12a, whic h had an ID50 of 9.0 mg kg(-1) in the CFE test, appeared to be the mos t efficient compound tested in this new series of non-carboxylic nonst eroidal anti-inflammatory drugs. Glycinamide 8a, although less potent in the same assay (14.3 mg kg(-1)), exerted a significant inhibitory e ffect in acute and chronic ear-swelling tests after topical applicatio n of 3 mg/ear. (C) Elsevier, Paris.