Development of a novel series of (2-quinolinylmethoxy)phenyl-containing compounds as high-affinity leukotriene receptor antagonists. 1. Initial structure-activity relationships

Article abstract of DOI:10.1021/jm00166a016

This series of reports describes the development of orally active, highly potent, specific antagonists of the peptidoleukotrienes containing a (2-quinolinylmethoxy)phenyl moiety. Described in this first report are the structure-activity relationships that led to more than a 20-fold improvement of the potency and selectivity of the initial chemical lead (RG 5901). From this series of compounds, RG 7152 (16) was identified and selected for further evaluation in the clinic as an antiasthmatic agent. Compound 16 competitively inhibits [³H]LTD₄ binding to membranes from guinea pigs lung (K(i) = 38 ± 6 nM) and the spasmogenic activity of LTC₄, LTD₄, and LTE₄ in parenchymal lung strips from guinea pigs. Unlike the original lead (RG 5901), compound 16 does not inhibit 5-lipoxygenase from guinea pig PMNs. Following oral administration to guinea pigs, 16 blocks LTD₄-induced dermal permeability (ED₅₀ = 6.9 mg/kg), LTD₄-induced bronchoconstriction (ED₅₀ = 1.1 mg/kg), antigen-induced bronchoconstriction (ED₅₀ = 2.5 mg/kg), and anaphylactic-induced mortality (ED₅₀ = 16 mg/kg). These studies on structure-activity relationships indicate that there is a requirement for an acidic function and the presence of the (2-quinolinylmethoxy)phenyl moiety in a specific geometric arrangement.