Modulation on C- and N-terminal moieties of a series of potent and selective linear tachykinin NK2 receptor antagonists

Article abstract of DOI:10.1002/cmdc.200900389

Herein we describe the synthesis of a series of new potent tachykinin NK₂ receptor antagonists by the modulation of the Cand N-terminal moieties of ibodutant (MEN 15596, 1). The Nterminal benzo[b]thiophene ring was replaced by different substituted naphthalenes and benzofurans, while further modifications were evaluated at the C-terminal tetrahydropyran moiety. Most compounds demonstrated a high affinity for the human NK₂ receptor and high in vitro antagonist potency, indicating that a wide range of substituents at both termini can be incorporated in the molecule without detrimental effects on the interactions with the NK₂ receptor. Selected compounds were tested in vivo confirming their activity as NK₂ antagonists. In particular, after both iv and id administration to guinea pig, compound 61b was able to antagonize NK₂-induced colonic contractions with a potency and duration-of-action fully comparable to the reference compound 1 (MEN 15596, ibodutant).