Design and synthesis of the potent, orally available, brain-penetrable arylpyrazole class of neuropeptide Y5 receptor antagonists.
Novel arylpyrazole derivatives were synthesized and evaluated as neuropeptide Y (NPY) Y5 receptor antagonists. Compound (-)-7, which features a novel chiral 2,3-dihydro-1H-cyclopenta[a]naphthalene moiety, showed good binding affinity and antagonistic activity for the Y5 receptor. After intracerebroventricular administration in SD rats, (-)-7 significantly inhibited food intake that was induced by the centrally administered Y5-preferring agonist, bovine pancreatic polypeptide, but had only a negligible effect on NPY-induced feeding.
Sato
Nagaaki
N
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo 3, Tsukuba 300-2611, Japan. satoung@banyu.co.jp
Takahashi
Toshiyuki
T
Shibata
Takunobu
T
Haga
Yuji
Y
Sakuraba
Aya
A
Hirose
Masaaki
M
Sato
Miki
M
Nonoshita
Katsumasa
K
Koike
Yuko
Y
Kitazawa
Hidefumi
H
Fujino
Naoko
N
Ishii
Yasuyuki
Y
Ishihara
Akane
A
Kanatani
Akio
A
Fukami
Takehiro
T
D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002417:Cattle; D004435:Eating / Q000187:drug effects; D006801:Humans; D007276:Injections, Intraventricular; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010191:Pancreatic Polypeptide / Q000494:pharmacology; D010539:Permeability; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D009281:Naphthalenes; D011720:Pyrazoles; D017476:Receptors, Neuropeptide Y; C100568:neuropeptide Y5 receptor; D010191:Pancreatic Polypeptide