Heteroarylmethoxyphenylalkoxyiminoalkylcarboxylic Acids as Leukotriene Biosynthesis Inhibitors

A novel series of heteroarylmethoxyphenylalkoxyiminoalkylcarboxylic acids was studied as leukotriene biosynthesis inhibitors. A hypothesis of structure−activity optimization by insertion of an oxime moiety was investigated using REV-5901 as a starting point. A systematic structure−activity optimization showed that the spatial arrangement and stereochemistry of the oxime insertion unit proved to be important for inhibitory activity. The promising lead, S-(E)-11, inhibited LTB4 biosynthesis in the intact human neutrophil with IC50 of 8 nM and had superior oral activity in vivo, in a rat pleurisy model (ED50 = 0.14 mg/kg) and rat anaphylaxis model (ED50 = 0.13 mg/kg). In a model of lung inflammation, S-(E)-11 blocked LTE4 biosynthesis (ED50 of 0.1 mg/kg) and eosinophil influx (ED50 of 0.2 mg/kg). S-(E)-11 (A-93178) was selected for further preclinical evaluation.