Modulation on C- and N-terminal moieties of a series of potent and selective linear tachykinin NK(2) receptor antagonists.
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).
Gensini
Martina
M
Chemistry Department, Menarini Ricerche S.p.A. Via Sette Santi 3, 50131 Florence, Italy.
Altamura
Maria
M
Dimoulas
Tula
T
Fedi
Valentina
V
Giannotti
Danilo
D
Giuliani
Sandro
S
Guidi
Antonio
A
Harmat
Nicholas J S
NJ
Meini
Stefania
S
Nannicini
Rossano
R
Pasqui
Franco
F
Tramontana
Manuela
M
Triolo
Antonio
A
Maggi
Carlo Alberto
CA
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
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