(6,7-Diaryldihydropyrrolizin-5-yl)acetic acids, a novel class of potent dual inhibitors of both cyclooxygenase and 5-lipoxygenase.
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 microM (CO); 0.18 microM (5-LO)) and 3n with a 4-OCH3 substituent (IC50 = 0.1 microM (CO); 0.24 microM (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 investigated in human cells.
Merckle GmbH, Blaubeuren, Germany.
S A
SA
Laufer
J
J
Augustin
G
G
Dannhardt
W
W
Kiefer
D000085:Acetates / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000085:Acetates; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D011758:Pyrroles