The airways pharmacology of DNK333, a potent, selective, non‐peptide dual NK1/NK2 receptor antagonist

Abstract

AbstractThe airways' pharmacology of DNK333 ((1R,3R,2E)‐N‐[3,4‐dichlorobenzyl)]‐4‐[(hexahydro‐2‐oxo‐1H‐azepin‐3‐yl)amino]‐N‐methyl‐3,5bis(trifluoromethyl) benzamide), a potent and selective dual NK1/NK2 neurokinin receptor antagonist is described in the present paper. DNK333 bound with high and similar affinities to human NK1 and NK2 receptors. In guinea‐pig isolated trachea, DNK333 induced concentration‐dependent blockade of the contractile responses to NK1‐ or NK2‐receptor agonists. In anaesthetized guinea‐pigs, DNK333 shifted the bronchoconstrictor dose‐response curves induced by NK1‐ and NK2‐receptor agonists by 21.8‐ (3 mg/kg) and 6.8‐fold (10 mg/kg), respectively. At 10 mg/kg, a 12‐h duration of action was observed. Nasal perfusion of substance P and capsaicin to anaesthetized guinea‐pigs induced extravasation, which was inhibited dose‐dependently by DNK333 (ED50 values 72 and 70 µg/kg, respectively). Exposure of conscious guinea‐pigs to 0.6 M citric acid resulted in cough and an increase in enhanced pause of respiratory function (Penh). Oral administration of DNK333 (0.3, 3, or 10 mg/kg, −2 h) inhibited cough by 62, 63, and 82%, respectively and the increase in Penh by 85.5 and 77.2% (3 and 10 mg/kg, respectively). Bronchoconstrictor responses in anaesthetized guinea‐pigs to intravenous injections of methacholine and substance P were increased 60 min after LPS challenge (1 mg/kg, i.v.). DNK333 (1 and 10 mg/kg) dosed intraduodenally 30 min prior to LPS challenge inhibited airway hyperreactivity in a dose‐dependent manner. In conclusion, DNK333 is a potent, orally bioavailable, dual NK1/NK2 receptor antagonist with a long duration of action. It inhibits bronchoconstriction, extravasation, cough, and airway hyperreactivity induced by endogenous release of neuropeptides, which renders DNK333 suitable for exploring the role of tachykinins in respiratory disease. Drug Dev Res 63:161–173, 2004. © 2004 Wiley‐Liss, Inc.