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

Abstract

The 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 NK 1 / NK 2 neurokinin receptor antagonist is described in the present paper. DNK333 bound with high and similar affinities to human NK 1 and NK 2 receptors. In guinea-pig isolated trachea, DNK333 induced concentrationdependent blockade of the contractile responses to NK 1 -or NK 2 -receptor agonists. In anaesthetized guineapigs, DNK333 shifted the bronchoconstrictor dose-response curves induced by NK 1 -and NK 2 -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 (ED 50 values 72 and 70 mg/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, À2 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 NK 1 /NK 2 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.

In vivo pharmacological evaluation of compound 48/80‐induced airways oedema by MRI

“…1 h before compound 48/80 challenge. In guinea pigs, intraduodenal administration of this dose of DNK333 has been shown to inhibit the SP‐induced bronchoconstriction when administered 30 min prior to endotoxin challenge ( Lewis et al ., 2004 ).…”

Capsaicin‐induced mucus secretion in rat airways assessed in vivo and non‐invasively by magnetic resonance imaging

“…inhibited chemoreflexes (apnea, bradycardia, and hypotension) induced by capsaicin. Oral administration of DNK333 (10 mg kg −1 ) has been shown to inhibit citric acid‐induced cough by 82% and SP‐induced bronchoconstriction when administered intraduodenally 30 min before endotoxin challenge in the guinea pig ( Lewis et al ., 2004 ). The affinity of DNK333 for the rat NK1 and NK2 receptors is of the same order as that for the guinea pig receptors (unpublished observations, Novartis Pharma Research).…”