Lucien Welin

Non-carboxylic antiinflammatory compounds. III: N-(4,6-dimethylpyridin-2-yl)arylcarboxamides and arylthiocarboxamides acting as brain edema inhibitors

Summary Pharmacomodulation of the non-carboxylic NSAID N -(4,6-dimethylpyridin-2-yl)benzamide 1 led to the synthesis of structurally related furan, thiophene and pyrrole carboxamides 3–14 . The derivatives benzenethiocarboxamides 15–18 and heteroaryl-thiocarboxamides 19–22 were also prepared by oxygen/sulfur exchange; this reaction was more efficiently carried out by P 4 S 10 than by Lawessons reagent. The 20 synthesized compounds were evaluated against peripheral edema by a foot-pad carrageenin-induced edema test. Amides 3–5, 8, 9, 11, 12 and 14 were most active, exhibiting > 90% inhibition after oral administration of 0.8 mmol·kg −1 . Two amides, 3 and 5 , were selected for evaluation of their inhibitory activity in PLA 2 -induced brain edema and were found to be more potent than dexamethasone after IP administration.

Pyrophtalones VII. Synthèse et activité anti-inflammatoire de (pyridinyl-4)-2 indanediones-1,3 substituées sur le noyau benzénique et/ou sur l'hétérocycle

Access routes to 2-(1,4-dihydro 4-pyridinylidene) indane-1,3-diones diversely substituted on the benzene ring are studied. The regiospecific attack of these β diketoenamines by alkyl iodides leads to N-substituted compounds. These derivatives may be obtained by any of three possible methods: (1) condensation of 4-methyl pyridine with ethyl phthalates in the absence of catalyst; (2) oxidative condensation of N-alkyl pyridinium bromides with indane-1,3-diones; (3) aminolysis of 2-(4-4H-pyranylidene) indane-1,3-diones. Pharmacomodulation by the introduction of oxygen or sulfur containing functions (ether, thioether, alcohol, ketone, acid, ester, amide) on the nitrogen of the basic molecule is not very fruitful; only the acetic derivative 19 manifests marked anti-inflammatory activity unaccompanied by anti-coagulant action. The presence of chloro, nitro or methoxyl groups on 5 after N-substitution by ethyl or piperidinylethyl groups appears to be more favorable. The most active compound 57 decreases prostaglandin production and leukocyte migration without affecting either cyclo-oxygenase or 5-lipoxygenase. Its interference, direct or indirect, with phospholipasic A2 activity may be envisaged in particular.

Non-acidic anti-inflammatory compounds: activity of N-(4,6-dimethyl-2-pyridinyl) benzamides and derivatives

The inhibition of the carragenin-induced rat-paw edema by previously synthesized N-(4,6-dimethyl)-2-pyridinyl) benzamides was evaluated. Among the 29 tested compounds, secondary benzamides 1, 12 and tertiary benzamide 60 exhibited a significant anti-inflammatory activity. It prompted us to envision a pharmacomodulation in this series by structural modifications on the homocycle, the amide function and the heterocycle. Although benzamide 38, acetamide 50 and benzylamine 56 elicited marked inhibitory activity, none was more active than N-(4,6-dimethyl-2-pyridinyl) benzamide 1. The mechanism of the anti-inflammatory action of 1 was investigated. The results showed that this molecule reduced eicosanoid biosynthesis but was unable to reduce cyclooxygenase or lipoxygenase activities. Although it did not directly block phospholipase activity, however, an inhibitory process at this level is likely.

Non-acidic antiinflammatory compounds II. Synthesis and activity of 6-amino-2,4-lutidine derivatives

Benzamides I, phenylalkanamides II and cinnamamides III are structurally related to the antiinflammatory N-(4,6-dimethylpyridin-2-yl)benzamide I. These were synthesized and the transformation of the 2-aminopyridine nucleus of benzamides I into a 2-imino-1,2-dihydropyridine structure (compounds IV) was also carried out. Of the 49 new derivatives, the 3-fluorobenzamide 9 was the most potent in the oral treatment of carrageenen-induced peripheral edema; IC50 = 12.2 mg·kg−1. It was 3 times as active as benzamide 1, but the latter nevertheless had a better therapeutic index (LD50/IC50) of 52 against 23. Benzamide 1, a non-acidic antiinflammatory compound devoid of any blocking activity on cyclooxygenase, markedly reduces the production of reactive oxygen species in rat peritoneal macrophages. This compound probably acts at the membrane, perhaps by interference with transmembrane events.

Antiinflammatory Mechanism of Cordiachromene A Action

The mechanism of antiinflammatory action of cordiachromene A, isolated from the chloromethylenic extract of the ascidian Aplidium antillense or chemically synthesized, was studied using different in vivo and in vitro inhibition tests on enzymes of the cyclooxygenase cascade. Cordiachromene A inhibits prostacyclin synthesis and arachidonic acid metabolism but not phospholipase A2 and peroxidase. The mechanism of action, already known to be stereospecific, operates by cyclooxygenase inhibition.

Effect of clonidine on experimental brain edema in the rat

Several experimental brain edema models are currently available for drug evaluation. Brain edemas are essentially vasogenic and/or cytotoxic, and eicosanoids are involved in the development of these edemas. Thus, a new model developed in our laboratory, which was obtained by phospholipase A2 intracerebral injection was used to study the antiinflammatory effect of clonidine. The copper wire edema model was chosen as reference.Edemas wer evaluated by determining the swelling and Na+ and K+ tissue concentrations of each hemisphere. Drugs were administered intraperitoneally.Dexamethasone was the only drug to inhibit copper wire-induced edema, whereas indomethacin and clonidine as well as dexamethasone exhibited marked antiedematous activity in our model. The effect of clonidine, which could be inhibited by prior administration of yohimbine, suggests that central α2 stimulation is involved in reducing experimental brain edema.

Marine Bioactive Compounds: Stereospecific Anti‐Inflammatory Activity of Natural and Synthetic Cordiachromene A

A new synthesis is proposed for cordiachromene A (CCA), a bioactive component of the ascidian Aplidium antillense Gravier, using a method producing a racemic mixture. The anti‐inflammatory activities of a natural extract and a chemically synthetic form of CCA were assessed in vivo by carrageenan‐induced rat‐paw edema. The activity of synthetic CCA was confirmed by a test on kaolin‐induced granuloma in the rat. Strong activities were measured for both CCA, but comparison of results of the first test suggests that only the natural optically active isomer has an anti‐inflammatory effect. CCA is similar to indomethacin in its effect on carrageenan‐induced rat‐paw edema and ten times as active as phenylbutazone.