120128-20-3

RG 12525 competitively inhibits ³ H-LTD4 binding to lung membranes (K _i = 3.0 +/- 0.3 nM) and competitively antagonizes the spasmogenic activity of LTC4, LTD4 and LTE4 on lung strips (KB values = 3 nM) with greater than 8000 fold selectivity. RG 12525 (2.5 µM or 25 µM) inhibits the microsomal activity of CYP2C9 and -3A4, but does not significantly inhibit CYP1A2,-2A6, -2C19, or -2D6. RG 12525 (25 µM) also causes a substantial amount of inhibition at the 5 and 10 µM midazolam concentrations.

RG 12525 orally inhibits LTD4 induced wheal formation (ED ₅₀ = 5 mg/kg with a t _1/2 = 10 hrs at 9 mg/kg), LTD4 induces bronchoconstriction (ED ₅₀ = 0.6 mg/kg), and anaphylactic death (ED ₅₀ = 2.2 mg/kg with a t _1/2 = 7 hrs at 10 mg/kg) and antigen induces bronchoconstriction (ED ₅₀ = 0.6 mg/kg). RG 12525 inhibits antigen-induced mortality in the systemic anaphylaxis model with an ED ₅₀ (95% confidence interval) = 2.2 (0.8-6.4) mg/kg. RG 12525 also protects against LTD4-induced bronchoconstriction in a model measuring changes in pulmonary function with an ED ₅₀ = 0.6 (0.4-1.0) mg/kg.