BAY X1005, a new selective inhibitor of leukotriene synthesis: pharmacology and pharmacokinetics.
The enantiomer BAY X1005 [(R)-2-[4-(quinolin-2-yl-methoxy)phenyl]-2-cyclopentyl acetic acid] potently inhibits LTB4 synthesis in isolated PMNL of various species (IC50 mumol/l, human 0.22, rat 0.026, mouse 0.039) and LTC4 synthesis in mouse macrophages (IC50 0.021 mumol/l). Due to high protein binding the in vitro potency for LTB4 synthesis inhibition in whole blood is lowered to 17 mumol/l as determined by RIA. BAY X1005 is selective for the 5-lipoxygenase pathway leaving 12-HETE and HHT unaltered, as determined in human whole blood. After oral application BAY X1005 inhibits edema formation and myeloperoxidase activity in the arachidonate-induced mouse ear inflammation test (ED50 48.7 and 7.9, respectively). Oral activity in the rat ex vivo is found in whole blood for LTB4 synthesis inhibition (ED50 11.8 mg/kg p.o.). BAY X1005 demonstrates a high bioavailability (f 86%) with a Cmax of 13 mg/l and t1/2 of 3.5 h in the rat at 10 mg/kg p.o. Thus, the pharmacodynamic, pharmacokinetic profile and safety aspects of the leukotriene synthesis inhibitor BAY X1005 allow testing in man for its therapeutic potential in inflammatory and allergic diseases.
Müller-Peddinghaus
R
R
Pharma Research Center, Bayer AG, Wuppertal, Germany.
Fruchtmann
R
R
Ahr
H J
HJ
Beckermann
B
B
Bühner
K
K
Fugmann
B
B
Junge
B
B
Matzke
M
M
Kohlsdorfer
C
C
Raddatz
S
S
D000284:Administration, Oral; D000818:Animals; D006801:Humans; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors; D051379:Mice; D009504:Neutrophils / Q000201:enzymology; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats
D016859:Lipoxygenase Inhibitors; D011804:Quinolines; C079315:2-(4-(quinolin-2-yl-methoxy)phenyl)-2-cyclopentylacetic acid; D007975:Leukotriene B4