67431-24-7Relevant articles and documents
Heteroarylmethoxyphenylalkoxyiminoalkylcarboxylic acids as leukotriene biosynthesis inhibitors
Kolasa, Teodozyj,Gunn, David E.,Bhatia, Pramila,Woods, Keith W.,Gane, Todd,Stewart, Andrew O.,Bouska, Jennifer B.,Harris, Richard R.,Hulkower, Keren I.,Malo, Peter E.,Bell, Randy L.,Carter, George W.,Brooks, Clint D. W.
, p. 690 - 705 (2007/10/03)
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.
