Title of article :
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 Original Research Article
Author/Authors :
Yuji Haga، نويسنده , , Toshihiro Sakamoto، نويسنده , , Takunobu Shibata، نويسنده , , Katsumasa Nonoshita، نويسنده , , Makoto Ishikawa، نويسنده , , Takuya Suga، نويسنده , , Hirobumi Takahashi، نويسنده , , Toshiyuki Takahashi، نويسنده , , Hidekazu Takahashi، نويسنده , , Makoto Ando، نويسنده , , Takashi Murai، نويسنده , , Akira Gomori، نويسنده , , Zenjun Oda، نويسنده , , Hidefumi Kitazawa، نويسنده , , Yuko Mitobe، نويسنده , , Maki Kanesaka، نويسنده , , Tomoyuki Ohe، نويسنده , , Hisashi Iwaasa، نويسنده , , Yasuyuki Ishii، نويسنده , , Akane Ishihara، نويسنده , , et al.، نويسنده ,
Abstract :
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 1 mg/kg. This compound was selected for proof-of-concept studies in human clinical trials.
Keywords :
Neuropeptide Y , NPY , Y5 receptor , Antagonist
