Pharmacological profile of MEN91507, a new CysLT1 receptor antagonist

MEN91507 (8-[2-(E)-[4-[4-(4-fluorophenyl)butyloxy]phenyl]vinyl]-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran sodium salt)) potently displaced [H-3]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 pK(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 ED50s, 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 mumol/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 mumol/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 D4 through the stimulation of CysLT(1) receptors. (C) 2002 Elsevier Science B.V. All rights reserved.