Discovery of novel, orally active dual NK1/NK2 antagonists.
Bernstein PR, Aharony D, Albert JS, Andisik D, Barthlow HG, Bialecki R, Davenport T, Dedinas RF, Dembofsky BT, Koether G, Kosmider BJ, Kirkland K, Ohnmacht CJ, Potts W, Rumsey WL, Shen L, Shenvi A, Sherwood S, Stollman D, Russell K.
Exploration of the SAR around selective NK2 antagonists, SR48968 and ZD7944, led to the discovery that naphth-1-amide analogues provide potent dual NK1 and NK2 antagonists. ZD6021 inhibited binding of [3H]-NKA or [3H]-SP to human NK1 and NK2 receptors, with high-affinity (K(i)=0.12 and 0.62nM, respectively). In functional assays ZD6021 had, at 10(-7)M, in human pulmonary artery pK(B)=8.9 and in human bronchus pK(B)=7.3, for NK1 and NK2, respectively. Oral administration of ZD6021 to guinea pigs dose-dependently attenuated ASMSP induced extravasation of plasma proteins, ED(50)=0.5mg/kg, and NK2 mediated bronchoconstriction, ED(50)=13mg/kg.