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Vol. 297, Issue 1, 458-466, April 2001

In Vitro and in Vivo Pharmacological Characterization of BIIL 284, a Novel and Potent Leukotriene B4 Receptor Antagonist

F. W. Birke, C. J. Meade, R. Anderskewitz, G. A. Speck and H.-M. Jennewein

Departments of Pulmonary Research (F.W.B., C.J.M., G.A.S., H.-M.J.) and Medicinal Chemistry (R.A.), Boehringer Ingelheim Pharma KG, Ingelheim, Germany

BIIL 284 is a new LTB4 receptor antagonist. It is a prodrug and has negligible binding to the LTB4 receptor. However, ubiquitous esterases metabolize BIIL 284 to the active metabolites BIIL 260 and BIIL 315, the glucuronidated form of BIIL 260. Both metabolites have high affinity to the LTB4 receptor on isolated human neutrophil cell membranes with Ki values of 1.7 and 1.9 nM, respectively. On vital human neutrophilic granulocytes Ki was around 1 nM. BIIL 260 and BIIL 315 interact with the LTB4 receptor in a saturable, reversible, and competitive manner. BIIL 260 and its glucuronide BIIL 315 also potently inhibited LTB4-induced intracellular Ca2+ release in human neutrophils (IC50 values of 0.82 and 0.75 nM, respectively) as measured with Fura-2. High efficacy of BIIL 284 has been demonstrated in various in vivo models. BIIL 284 inhibited LTB4-induced mouse ear inflammation with ED50 = 0.008 mg/kg p.o., LTB4-induced transdermal chemotaxis in guinea pigs with ED50 = 0.03 mg/kg p.o., LTB4-induced neutropenia in various species (monkey: ED50 = 0.004 mg/kg p.o.), and LTB4-induced Mac1-expression in monkeys (ED50 = 0.05 mg/kg p.o. in Tylose). Full blockade of LTB4 receptors over 24 h was achieved by 0.3 mg/kg BIIL 284 after single oral dose as measured by LTB4-induced neutropenia or Mac1-expression in the monkey model. BIIL 284 is an unusually potent and long-acting orally active LTB4 antagonist, and is therefore under clinical development as a novel anti-inflammatory principle.

0022-3565/01/2971-0458$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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