Abstract

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 K_i values of 1.7 and 1.9 nM, respectively. On vital human neutrophilic granulocytesK_i 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 LTB₄antagonist, and is therefore under clinical development as a novel anti-inflammatory principle.