title: BAY X1005, a new inhibitor of leukotriene synthesis: in vivo inflammation pharmacology and pharmacokinetics.
abstract: (R)-2-[4-(quinolin-2-yl-methoxy)phenyl]-2-cyclopentyl acetic acid) (BAY X1005) is an orally active inhibitor of the synthesis of the leukotrienes B4 and C4 in selected animal models that effectively reduces the vascular phenomena of inflammation, i.e., edema formation and leukocyte immigration. The arachidonic acid-induced mouse ear inflammation test allowed the evaluation of the antiedematous effects of BAY X1005 after topical (ED50, 18 micrograms/ear) and oral (ED50, 48.7 mg/kg) administration. Profound inhibition of myeloperoxidase activity as a marker for phagocyte infiltration was seen (ED50, 3 micrograms/ear topically and 7.9 mg/kg p.o.) even 5 hr after application. The platelet-activating factor-induced death of mice was statistical significantly and dose-dependently reduced (100 mg/kg p.o.; mean, 51%). BAY X1005 had no analgesic properties in the phenyl-benzoquinone writhing test in mice and only limited efficacy in the baker's yeast-induced hyperalgesia test in the rat (ED50, 90 mg/kg p.o.), although cyclooxygenase inhibitors (indomethacin ED50, 1.7 mg/kg p.o.) are very potent. In another cyclooxygenase-sensitive test, the carrageenan-induced edema and the baker's yeast-induced fever in the rat, BAY X1005 was virtually devoid of any activity. The rat whole blood ex vivo leukotriene B4 inhibition assay demonstrated that BAY X1005 was potent (ED50, 11.8 and 6.7 mg/kg p.o. at 1 and 5 hr, respectively) and had a long duration of action (16-hr ED40, 70 mg/kg p.o.). Similarly, inhibition of the zymosan-induced exudate leukotrienes B4 and C4 inhibition confirmed these data (ED50, 8.3 and 10.5 mg/kg p.o., respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Pharma Research Center, Bayer AG, Wuppertal, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Müller-Peddinghaus
authors.forename: C
authors.initials: C
authors.lastname: Kohlsdorfer
authors.forename: P
authors.initials: P
authors.lastname: Theisen-Popp
authors.forename: R
authors.initials: R
authors.lastname: Fruchtmann
authors.forename: E
authors.initials: E
authors.lastname: Perzborn
authors.forename: B
authors.initials: B
authors.lastname: Beckermann
authors.forename: K
authors.initials: K
authors.lastname: Bühner
authors.forename: H J
authors.initials: HJ
authors.lastname: Ahr
authors.forename: K H
authors.initials: KH
authors.lastname: Mohrs
mesh_terms: D000818:Animals; D001681:Biological Assay; D004487:Edema / Q000139:chemically induced; D005260:Female; D015289:Leukotrienes / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010972:Platelet Activating Factor / Q000633:toxicity; D010998:Pleurisy / Q000503:physiopathology; D011485:Protein Binding; D011804:Quinolines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats
chemical_list: D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D010972:Platelet Activating Factor; D011804:Quinolines; C079315:2-(4-(quinolin-2-yl-methoxy)phenyl)-2-cyclopentylacetic acid