New N-(pyridin-4-yl)-(indol-3-yl)acetamides and propanamides as antiallergic agents.
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.
Department of Organic Chemistry and Medicinal Chemistry, Faculty of Pharmacy, 44035 Nantes Cedex 01, France.
C
C
Menciu
M
M
Duflos
F
F
Fouchard
G
G
Le Baut
P
P
Emig
U
U
Achterrath
I
I
Szelenyi
B
B
Nickel
J
J
Schmidt
B
B
Kutscher
E
E
Günther
D000109:Acetylcholine / Q000276:immunology; D000818:Animals; D018926:Anti-Allergic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018893:Bronchoalveolar Lavage; D002199:Capillary Permeability / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D004802:Eosinophilia / Q000276:immunology; D006168:Guinea Pigs; D006636:Histamine Release / Q000187:drug effects; D006967:Hypersensitivity / Q000276:immunology; D066298:In Vitro Techniques; D007210:Indoleacetic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors; D015848:Interleukin-5 / Q000037:antagonists & inhibitors; D008297:Male; D008407:Mast Cells / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010529:Peritoneal Cavity / Q000166:cytology; D053284:Polyunsaturated Alkamides; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012221:Rhinitis, Allergic, Perennial / Q000276:immunology / Q000517:prevention & control; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects / Q000276:immunology / Q000502:physiology
D018926:Anti-Allergic Agents; D007210:Indoleacetic Acids; D015848:Interleukin-5; C117659:N-(pyridin-4-yl)-(1-(4-fluorobenzyl)indol-3-yl)acetamide; D053284:Polyunsaturated Alkamides; D011725:Pyridines; D015847:Interleukin-4; D002217:Carbachol; D000109:Acetylcholine