New N-(pyridin-4-yl)-(indol-3-yl)acetamides and propanamides as antiallergic agents.

C Menciu, M Duflos, F Fouchard, G Le Baut, P Emig, U Achterrath, I Szelenyi, B Nickel, J Schmidt, B Kutscher, E Günther

Department of Organic Chemistry and Medicinal Chemistry, Faculty of Pharmacy, 44035 Nantes Cedex 01, France.

Journal of medicinal chemistry 1999 Feb 25

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A series of new N-(pyridin-4-yl)-(indol-3-yl)alkylamides 44-84 has been prepared in the search of novel antiallergic compounds. Synthesis of the desired ethyl (2-methyindol-3-yl)acetates 1-4 was achieved by indolization under Fischer conditions; Japp-Klingemann method followed by 2-decarboxylation afforded the ethyl (indol-3-yl)alkanoates 17-25. Amidification was successfully carried out by condensation of the corresponding acids or their N-aryl(methyl) derivatives with 4-aminopyridine promoted by 2-chloro-1-methylpyridinium iodide. Efforts to improve the antiallergic potency of the title series by variation of the indole substituents (R1, R2, R) and the length of the alkanoic chain (n = 1, 2, 3) led to the selection of N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]acetamide 45, out of 41 compounds. This amide was 406-fold more potent than astemizole in the ovalbumin-induced histamine release assay, using guinea pig peritoneal mast cells, with an IC50 = 0.016 microM. Its inhibitory activity in IL-4 production test from Th-2 cells was identical to that of the reference histamine antagonist (IC50 = 8.0 microM) and twice higher in IL-5 assay: IC50 = 1.5 and 3.3 microM, respectively. In vivo antiallergic activity evaluation confirmed efficiency of 45 in sensitized guinea pig late phase eosinophilia inhibition, after parenteral and oral administration at 5 and 30 mg/kg, respectively. Its efficiency in inhibition of microvascular permeability was assessed in two rhinitis models; ovalbumin and capsaicin-induced rhinorrhea could be prevented after topical application of submicromolar concentrations of 45 (IC50 = 0.25 and 0.30 microM); and it also exerted significant inhibitory effect in the first test after iv and oral administration, with ID50 = 0.005 and 0.46 mg/kg.

Citation

C Menciu, M Duflos, F Fouchard, G Le Baut, P Emig, U Achterrath, I Szelenyi, B Nickel, J Schmidt, B Kutscher, E Günther. New N-(pyridin-4-yl)-(indol-3-yl)acetamides and propanamides as antiallergic agents. Journal of medicinal chemistry. 1999 Feb 25;42(4):638-48