title: Modulation on C- and N-terminal moieties of a series of potent and selective linear tachykinin NK(2) receptor antagonists.
abstract: Herein we describe the synthesis of a series of new potent tachykinin NK(2) receptor antagonists by the modulation of the C- and N-terminal moieties of ibodutant (MEN 15596, 1). The N-terminal 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 NK(2) 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 NK(2) receptor. Selected compounds were tested in vivo confirming their activity as NK(2) antagonists. In particular, after both iv and id administration to guinea pig, compound 61 b was able to antagonize NK(2)-induced colonic contractions with a potency and duration-of-action fully comparable to the reference compound 1 (MEN 15596, ibodutant).
authors: Chemistry Department, Menarini Ricerche S.p.A. Via Sette Santi 3, 50131 Florence, Italy.
authors: Martina
authors: M
authors: Gensini
authors: Maria
authors: M
authors: Altamura
authors: Tula
authors: T
authors: Dimoulas
authors: Valentina
authors: V
authors: Fedi
authors: Danilo
authors: D
authors: Giannotti
authors: Sandro
authors: S
authors: Giuliani
authors: Antonio
authors: A
authors: Guidi
authors: Nicholas J S
authors: NJ
authors: Harmat
authors: Stefania
authors: S
authors: Meini
authors: Rossano
authors: R
authors: Nannicini
authors: Franco
authors: F
authors: Pasqui
authors: Manuela
authors: M
authors: Tramontana
authors: Antonio
authors: A
authors: Triolo
authors: Carlo Alberto
authors: CA
authors: Maggi
mesh_terms: D000818:Animals; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C516535:6-methylbenzo(b)thiophene-2-carboxylic acid (1-(2-phenyl-((1-(tetrahydropyran-4-ylmethyl)piperidin-4-ylmethyl)carbamoyl)ethylcarbamoyl)cyclophenyl)amide; D004151:Dipeptides; D018041:Receptors, Neurokinin-2; D013876:Thiophenes; C088015:benzothiophene