CI-949: a new, potential antiallergy compound inhibits antigen-induced allergic reactions in guinea-pigs in vitro and in vivo.
CI-949 (5-methoxy-3-(1-methyl-ethoxy)-1-phenyl-N-1H-tetrazol-5-yl-1H -indole-2-carboxamide) effectively inhibited the release of histamine and the synthesis or release of immunoreactive sulfidopeptide leukotrienes C4-D4 and thromboxane B2 from antigen-challenged lung fragments of of actively sensitized guinea-pigs. The IC50s were 26.7 +/- 2.8 microM for histamine, 2.7 +/- 2.4 microM for leukotriene, and 3.0 +/- 1.8 microM for thromboxane. Drugs including ketotifen, cromolyn and nedocromil did not inhibit histamine release or did so only at high concentrations, and only cromolyn inhibited the synthesis or releases of the 2 eicosanoids. A dose of 50 mg/kg i.p. of CI-949 protected conscious, aerosol-allergen challenged guinea-pigs for at least 1 h and 100 mg/kg i.p. or per os protected for at least 2 h. These results, the comparisons to standard antiallergic drugs, and other data from experiments with human lung fragments and isolated peripheral leukocytes 1,2,3,4 suggest that CI-949 should be evaluated for clinical activity against allergic and inflammatory conditions in which histamine, sulfidopeptide leukotrienes, and/or thromboxane mediate symptoms.
Adolphson
R L
RL
Department of Experimental Therapy, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
Thueson
D O
DO
Finkel
M P
MP
Chestnut
J C
JC
Conroy
M C
MC
D000707:Anaphylaxis / Q000276:immunology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D000941:Antigens / Q000276:immunology; D004205:Cromolyn Sodium / Q000627:therapeutic use; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000627:therapeutic use*; D007114:Immunization; D066298:In Vitro Techniques; D007211:Indoles / Q000627:therapeutic use*; D007665:Ketotifen / Q000627:therapeutic use; D015394:Molecular Structure; D017835:Nedocromil; D015363:Quinolones / Q000627:therapeutic use; D012130:Respiratory Hypersensitivity / Q000188:drug therapy* / Q000276:immunology; D013777:Tetrazoles / Q000627:therapeutic use*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000941:Antigens; D006633:Histamine Antagonists; D007211:Indoles; D015363:Quinolones; D013777:Tetrazoles; D017835:Nedocromil; C061320:CI 949; D004205:Cromolyn Sodium; D007665:Ketotifen