Synthesis and evaluation of a novel series of pyrrolizine derivatives as dual cyclooxygenase-1 and 5-lipoxygenase inhibitors.
The aim of our study was to investigate structure activity relationship following the replacement of the 6-phenyl substituent at the 6,7-diaryl-2,3-dihydropyrrolizine template by various heteroaromatic residues. In this context we developed a new, efficient, and highly sensitive test method for the screening of dual cyclooxygenase-1 (COX-1) and 5-lipoxygenase (5-LOX) inhibitors. We used human platelets as a source of COX-1 and human PMNLs as a source of 5-LOX. Both cell types were isolated from the same volume of blood. PGE2 and LTB4 respectively were determined by highly selective and sensitive ELISA kits, using monoclonal antibodies. For a single determination at most 0.5 mL whole blood is needed.
Laufer
S
S
Department Drug Research, Merckle GmbH, Blaubeuren, Germany.
Striegel
H G
HG
Neher
K
K
Zechmeister
P
P
Donat
C
C
Stolingwa
K
K
Baur
S
S
Tries
S
S
Kammermeier
T
T
Dannhardt
G
G
Kiefer
W
W
D001094:Arachidonate 5-Lipoxygenase / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D051545:Cyclooxygenase 1; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects*; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D011758:Pyrroles; D001094:Arachidonate 5-Lipoxygenase; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D011451:Prostaglandin-Endoperoxide Synthases