MEN15596, a novel nonpeptide tachykinin NK2 receptor antagonist

Abstract: The pharmacological profile of MEN15596 or (6-methyl-benzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-1R-{[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide), a novel potent and selective tachykinin NK2 receptor antagonist endowed with oral activity, is described. At the human recombinant tachykinin NK2 receptor, MEN15596 showed subnanomolar affinity (pK i 10.1) and potently antagonized (pK B 9.1) the neurokinin A-induced intracellular calcium release. MEN15596 selectivity for the tachykinin NK2 receptor was assessed by binding studies at the recombinant tachykinin NK1 (pK i 6.1) and NK3 (pK i 6.4) receptors, and at a number of 34 molecular targets including receptors, transporters and ion channels. In isolated smooth muscle preparations MEN15596 showed a marked species selectivity at the tachykinin NK2 receptor with the highest antagonist potency in guinea-pig colon, human and pig bladder (pK B 9.3, 9.2 and 8.8, respectively) whereas it was three orders of magnitude less potent in the rat and mouse urinary bladder (pK B 6.3 and 5.8, respectively). In agreement with binding experiments, MEN15596 showed low potency in blocking selective NK1 or NK3 receptor agonist-induced contractions of guinea-pig ileum preparations (pA2 ≤6). In anaesthetized guinea-pigs, MEN15596 inhibited in a dose-related and persistent manner colon contractions induced by the selective tachykinin NK2 receptor agonist, [βAla8]neurokinin A(4–10) (3 nmol/kg i.v.), either after intravenous (ED50 0.18 μmol/kg), intraduodenal (ED50 3.16 μmol/kg) or oral administration (10–30 μmol/kg) without affecting, at 3 μmol/kg, i.v., the colonic contractions produced by the NK1 receptor selective agonist [Sar9]substance P sulfone (3 nmol/kg i.v.). In addition MEN15596 was effective in inhibiting bronchoconstriction produced by i.v. administration of [βAla8]neurokinin A(4–10). Overall the results indicate that MEN15596 is a potent and selective tachykinin NK2 receptor antagonist possessing high affinity and potency for guinea-pig, pig and human receptor, long duration of action in in vivo experiments and good oral bioavailability. [Copyright &y& Elsevier]