CI-949

CI-949 is an allergic mediator release inhibitor, which inhibits histamine, leukotriene C₄/D₄ (LTC₄/LTD₄), and thromboxane B₂ (TXB₂) release with IC₅₀s of 11.4 μM, 0.5 μM and 0.1 μM, respectively. IC50 & Target: IC50: 11.4 μM (Histamine), 0.5 μM (LTC₄/LTD₄), 0.1 μM (TXB₂)^[1] In Vitro: CI-949 inhibits, in a dose-dependent manner, the release of histamine, leukotriene, and thromboxane from human basophilic leukocytes challenged with anti-IgE. The IC₅₀ for inhibition of histamine release is 11.4 μM. Virtually complete inhibition of histamine release occurs at 100 μM, with negligible inhibition of release <3 μM. Both LTC₄/LTD₄ and TXB₂ release are inhibited at lower concentrations (IC₅₀, 0.5 and 0.1 μM, respectively). Complete inhibition of leukotriene and thromboxane synthesis/release is obtained with 10 and 1 μM of CI-949, respectively. CI-949 is an effective inhibitor of release of all three mediators in response to this stimulus. The IC₅₀s for inhibition of histamine, leukotriene, and thromboxane are 6.3, 2, and 0.1 μM for FMLP challenge^[1]. CI-949 effectively inhibits 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 are 26.7±2.8 μM for histamine, 2.7±2.4 μM for leukotriene, and 3.0±1.8 μM for thromboxane^[2]. In Vivo: Actively sensitized guinea-pigs are given i .p. doses of 30, 50, or 100 mg/kg of CI-949 between 20-120 min before aerosol challenge with antigen. A dose of 50 mg/kg i.p. of CI-949 protects conscious, aerosol-allergen challenged guinea-pigs for at least 1 h and 100 mg/kg i.p. or per os protects for at least 2 h. The animals are protected from collapse for at least I h after 50 and 100 mg/kg, and 100 mg/kg afforded complete protection up to 2h. An oral dose of 100 mg/kg at 2 h, but not at 4 h before challenge also inhibits collapse. A dose of 100 mg/kg at 4 h and again at 2 h before challenge is more effective than a single dose at 2 h^[2].