197894-84-1

CI-1044 is an orally active PDE4 inhibitor with IC ₅₀ s of 0.29, 0.08, 0.56, 0.09 μM for PDE4A5, PDE4B2, PDE4C2 and PDE4D3, respectively. CI-1044 selectively inhibits PDE4 crude extract from U937 cells with an IC ₅₀ value of 0.27±0.02 μM being threefold more potent than rolipram (IC ₅₀ =0.91±0.14) and tenfold less potent than cilomilast (IC ₅₀ =0.026±0.007) in the same assay. In the presence of PDE4 inhibitors, the production of TNF-α is dose dependently decreased with mean IC ₅₀ values from three separate experiments of 0.31±0.05, 0.26±0.05 and 0.11±0.01 μM, for CI-1044, cilomilast and rolipram, respectively.

TNF-α production is dose-dependently inhibited by CI-1044, rolipram and cilomilast with ID ₅₀ s of 0.4, 1.4 and 1.6 mg/kg respectively following single oral administration. Following repeated administration with CI-1044, the ID ₅₀ value represents 0.5 mg/kg p.o.. CI-1044 plasma levels increase proportionally with doses ranging between 0.1 and 40 mg/kg p.o. (R2=0.878). CI-1044 dose dependently inhibits the accumulation of eosinophils in Bronchoalveolar lavages (BAL) fluids with an ID ₅₀ value of 3.25 mg/kg. A single dose treatment with CI-1044 (10 mg/kg, p.o.) 24, 8, 3 or 1 h before the antigen challenge induces 6, 56, 48 and 79% inhibition in the number of eosinophils in BAL.