In vitro pharmacology of BAY X1005, a new inhibitor of leukotriene synthesis.
BAY X1005, (R)-2-[4-(quinolin-2-yl-methoxy)phenyl]-2-cyclopentyl acetic acid, is an enantioselective inhibitor of leukotriene biosynthesis. It effectively inhibits the synthesis of LTB4 in A23187-stimulated leukocytes from rats, mice and humans (IC50 0.026, 0.039 and 0.22 mumol/l, respectively) as well as the formation of LTC4 (IC50 0.021 mumol/l) in mouse peritoneal macrophages stimulated with opsonized zymosan. The compound is, however, less active in inhibiting LTB4 synthesis in human whole blood (IC50 17.0 and 11.6 mumol/l, as measured by RIA or HPLC, respectively). BAY X1005 exhibits a high enantioselectivity in human whole blood (31 times over the (S)-enantiomer). BAY X1005 is shown to be a selective inhibitor of the formation of 5-lipoxygenase-derived metabolites in vitro, without effects on other routes of arachidonic acid metabolism such as 12-lipoxygenase in human whole blood and cyclooxygenase in both mouse macrophages and human whole blood. BAY X1005 is devoid of any antioxidant activity (methemoglobin induction and xanthine-xanthine oxidase assay), without effects on granule release and with only weak effects on reactive oxygen species generation in human PMNL.
Fruchtmann
R
R
Pharmaceutical Research Center, Bayer AG, Wuppertal, FRG.
Mohrs
K H
KH
Hatzelmann
A
A
Raddatz
S
S
Fugmann
B
B
Junge
B
B
Horstmann
H
H
Müller-Peddinghaus
R
R
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D006801:Humans; D007975:Leukotriene B4 / Q000096:biosynthesis*; D017997:Leukotriene C4 / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D008706:Methemoglobin / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013237:Stereoisomerism; D014969:Xanthine Oxidase / Q000378:metabolism; D015054:Zymosan / Q000494:pharmacology
D016859:Lipoxygenase Inhibitors; D011804:Quinolines; D017382:Reactive Oxygen Species; C079315:2-(4-(quinolin-2-yl-methoxy)phenyl)-2-cyclopentylacetic acid; D007975:Leukotriene B4; D016718:Arachidonic Acid; D017997:Leukotriene C4; D000001:Calcimycin; D008706:Methemoglobin; D015054:Zymosan; D014969:Xanthine Oxidase