Design, synthesis, and SAR of tachykinin antagonists: Modulation of balance in NK1/NK2 receptor antagonist activity

Article abstract of DOI:10.1021/jm020094i

Through optimization of compounds based on the dual NK₁/NK₂ antagonist ZD6021, it was found that alteration of two key regions could modulate the balance of NK₁ and NK₂ potency. Substitution of the 2-naphthalene position in analogues of ZD6021 resulted in increased NK₁ potency and thus afforded NK₁ preferential antagonists. Alterations of the piperidine region could then increase NK₂ potency to restore dual NK₁/NK₂ selectivity. Through these efforts, three novel receptor antagonists from a single chemically related series were identified; two are dual NK₁/NK₂ antagonists, and the third is an NK₁ preferential antagonist. In this paper, the factors affecting the balance of NK₁ and NK₂ selectivity in this series are discussed and the in vitro and in vivo properties of the novel antagonists are described.