Discovery of novel, orally active dual NK 1/NK 2 antagonists

Abstract

Exploration of the SAR around selective NK 2 antagonists, SR48968 and ZD7944, led to the discovery that naphth-1-amide analogues provide potent dual NK 1 and NK 2 antagonists. ZD6021 inhibited binding of [ 3H]-NKA or [ 3H]-SP to human NK 1 and NK 2 receptors, with high-affinity ( K i=0.12 and 0.62 nM, respectively). In functional assays ZD6021 had, at 10 −7 M, in human pulmonary artery p K B=8.9 and in human bronchus p K B=7.3, for NK 1 and NK 2, respectively. Oral administration of ZD6021 to guinea pigs dose-dependently attenuated ASMSP induced extravasation of plasma proteins, ED 50=0.5 mg/kg, and NK 2 mediated bronchoconstriction, ED 50=13 mg/kg.