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.
Pharma Research Center, Bayer AG, Wuppertal, Germany.
R
R
Müller-Peddinghaus
R
R
Fruchtmann
H J
HJ
Ahr
B
B
Beckermann
K
K
Bühner
B
B
Fugmann
B
B
Junge
M
M
Matzke
C
C
Kohlsdorfer
S
S
Raddatz
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