A Novel Dual Antagonist of Thromboxane A₂ and Leukotriene D₄ Receptors: Synthesis and Structure–Activity Relationships of Chloroquinolylvinyl Derivatives

抄録

To discover an orally active thromboxane A₂ (TXA₂) and leukotriene D₄ (LTD₄) dual antagonist, we designed and synthesized chloroquinolylvinyl derivatives based on the structures of the TXA₂ antagonist daltroban and the LTD₄ antagonist montelukast. Among these derivatives, 4-{[(2-(4-chlorophenylsulfonylamino)-1-{3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}ethyl)thio]methyl}benzoic acid (18d) showed potent inhibitory activity against U46619-induced aggregation of guinea pig platelets and LTD₄-induced contraction in the guinea pig ileum, with IC₅₀ values of 340 nm and 0.40 nm, respectively. Oral administration of 18 d also inhibited both the LTD₄-induced acceleration of plasma leakage to skin in guinea pig and the U46619-induced increase in airway resistance in guinea pig with ED₅₀ values of 0.47 mg/kg and 3.3 mg/kg, respectively.