Discovery of trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, a potent and orally active neuropeptide Y Y5 receptor antagonist.
A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide derivatives were synthesized to identify potent NPY Y5 receptor antagonists. Of the compounds, 21j showed high Y5 binding affinity, metabolic stability and brain and cerebrospinal fluid (CSF) penetration, and low susceptibility to P-glycoprotein transporters. Oral administration of 21j significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 1mg/kg. This compound was selected for proof-of-concept studies in human clinical trials.
Haga
Yuji
Y
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba 300-2611, Japan.
Sakamoto
Toshihiro
T
Shibata
Takunobu
T
Nonoshita
Katsumasa
K
Ishikawa
Makoto
M
Suga
Takuya
T
Takahashi
Hirobumi
H
Takahashi
Toshiyuki
T
Takahashi
Hidekazu
H
Ando
Makoto
M
Murai
Takashi
T
Gomori
Akira
A
Oda
Zenjun
Z
Kitazawa
Hidefumi
H
Mitobe
Yuko
Y
Kanesaka
Maki
M
Ohe
Tomoyuki
T
Iwaasa
Hisashi
H
Ishii
Yasuyuki
Y
Ishihara
Akane
A
Kanatani
Akio
A
Fukami
Takehiro
T
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002555:Cerebrospinal Fluid / Q000378:metabolism; D004355:Drug Stability; D004435:Eating / Q000187:drug effects; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; D000577:Amides; D001572:Benzofurans; D017476:Receptors, Neuropeptide Y; D013141:Spiro Compounds; C100568:neuropeptide Y5 receptor; C105430:benzofuran