(6,7-Diaryldihydropyrrolizin-5-yl)acetic Acids, a Novel Class of Potent Dual Inhibitors of Both Cyclooxygenase and 5-Lipoxygenase

Article abstract of DOI:10.1021/jm00038a021

A novel class of nonantioxidant dual inhibitors of both CO and 5-LO is described.The balance between the activity against CO and 5-LO can be shifted by modifying the substitution pattern of the phenyl moiety at the 6-position of the pyrrolizine ring.Structure-activity relationships are discussed.Compound 3e with a 4-Cl substituent (IC50 = 0.21 μM (CO); 0.18 μM (5-LO)) and 3n with a 4-OCH3 substituent (IC50 = 0.1 μM (CO); 0.24 μM (5-LO)) are the most potent and well-balanced dual inhibitors of both enzymes.The inhibition of CO was determined in a bovine thrombocyte intact cell assay and that of 5-LO using intact bovine PMNL.Compound 3e was also ivestigated in human cells.