Heteroarylmethoxyphenylalkoxyiminoalkylcarboxylic acids as leukotriene biosynthesis inhibitors

A novel series of heteroarglmethoxyphenylalkoxyiminoalkylcarboxylic acids w as studied as leukotriene biosynthesis inhibitors. A hypothesis of structur e-activity optimization by insertion of an oxime moiety was investigated us ing REV-5901 as a starting point. A systematic structure-activity optimizat ion showed that the spatial arrangement and stereochemistry of the oxime in sertion 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.