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

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  • A Novel Dual Antagonist of Thromboxane A2 and Leukotriene D4 Receptors: Synthesis and Structure-Activity Relationships of Chloroquinolylviny Derivatives
  • Novel Dual Antagonist of Thromboxane A2 and Leukotriene D4 Receptors Synthesis and Structure Activity Relationships of Chloroquinolylviny Derivatives

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Abstract

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.

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