Pharmacological profile of MEN91507, a new CysLT 1 receptor antagonist

Abstract

MEN91507 (8-[2-( E)-[4-[4-(4-fluorophenyl)butyloxy]phenyl]vinyl]-4-oxo-2-(5-1 H-tetrazolyl)-4 H-1-benzopyran sodium salt)) potently displaced [ 3H]leukotriene D 4 binding from guinea-pig lung and dimethylsulphoxide-differentiated U937 (dU937) cell membranes ( K i 0.50±0.16 and 0.65±0.29 nM, respectively). On the other hand, MEN91507 did not display significant binding affinity for a series of receptors or channels. In functional studies on dU937 cells, MEN91507 behaved as insurmountable antagonist of leukotriene D 4-induced calcium transients, with an apparent p K B of 10.25±0.15. In anaesthetized guinea-pigs, MEN91507 antagonized in a dose-dependent manner leukotriene D 4-induced bronchoconstriction following i.v. or oral administration: the ED 50s were 3.0±0.3 and 140±90 nmol/kg, respectively. The inhibition of leukotriene D 4-induced bronchoconstriction by MEN91507 was long-lasting, since a dose of 0.6 μmol/kg produced 74% reduction of the response after 8 h from administration. Likewise, leukotriene D 4-induced microvascular leakage was antagonized by MEN91507 either following i.v. or oral administration: a significant inhibitory effect was still evident at 16 h from oral administration of a dose of 6 μmol/kg. It is concluded that MEN91507 is a potent and selective antagonist of both guinea-pig and human CysLT 1 receptors; in addition, in vivo studies on guinea-pigs indicate that MEN91507 is an orally available and long-lasting antagonist of the bronchomotor and pro-inflammatory effects induced by leukotriene D 4 through the stimulation of CysLT 1 receptors.