BAY-X1005, A NEW SELECTIVE INHIBITOR OF LEUKOTRIENE SYNTHESIS - PHARMACOLOGY AND PHARMACOKINETICS

The enantiomer BAY X1005 2-[4-(quinolin-2-yl-methoxy)phenyl]-2-cyclo-p entyl acetic acid} potently inhibits LTB4 synthesis in isolated PMNL o f various species (IC50 mumol/l, human 0.22, rat 0.026, mouse 0.039) a nd LTC4 synthesis in mouse macrophages (IC50 0.021 mumol/l). Due to hi gh protein binding the in vitro potency for LTB4 synthesis inhibition in whole blood is lowered to 17 mumol/l as determined by RIA. BAY X100 5 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 bloo d for LTB4 synthesis inhibition (ED50 11.8 mg/kg p.o.). BAY X1005 demo nstrates a high bioavailability (f 86%) with a C(max) of 13 mg/l and t 1/2 of 3.5 h in the rat at 10 mg/kg p.o. Thus, the pharmacodynamic, ph armacokinetic profile and safety aspects of the leukotriene synthesis inhibitor BAY X1005 allow testing in man for its therapeutic potential in inflammatory and allergic diseases.