Pharmacological properties of novel LTC4 synthase inhibitor

Rational: AZD9898 is a small molecule inhibitor of leukotriene C4 synthase (LTC4S) in development for oral treatment of leukotriene driven asthma. AZD9898 is expected to inhibit the downstream production of CysLTs but, unlike the 5-LO inhibitor Zileuton, spare the production of LTB4 and the pro-resolving lipoxins. Hence, AZD9898 has the potential to give additional benefits in asthma compared to leukotriene modifiers on the market. Here we describe the pharmacological properties of AZD9898. Methods: The PK/PD properties and potency of the LTC4S inhibitor AZD9898 was tested in vivo in rat and in vitro in recombinant enzyme assays, human PBMCs, eosinophils and mast cells upon stimulation. Ex vivo stimulation of human whole blood and nasal polyp tissue was used for additional proof of mechanism in human tissue and for investigation of a differentiated profile of AZD9898 compared to CysLT inhibitors currently on the market. Results: The potency of AZD9898 was in the nanomolar range in enzyme assays, rat airways and human PBMCs. AZD9898 completely inhibited LTC4 production in eosinophils and mast cells and showed a differentiated profile compared to current leukotriene modifiers in explant assays of human whole blood and nasal polyps, by inhibiting CysLTs while sparing LTB4 and the pro-resolving lipoxins. There was a direct relationship between plasma concentrations of AZD9898 and CysLT inhibition in the airways of rats. Conclusions: AZD9898 effectively inhibits CysLT production in vivo and in vitro and shows favorable pharmacological properties. LTC4 synthase may be the preferred point at to which inhibit cysteinyl leukotrienes in asthma patients and will be taken forward in clinical studies.