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.

Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba 300-2611, Japan.

Bioorganic & medicinal chemistry 2009 Oct 1

filter terms:

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.

Citation

Yuji Haga, Toshihiro Sakamoto, Takunobu Shibata, Katsumasa Nonoshita, Makoto Ishikawa, Takuya Suga, Hirobumi Takahashi, Toshiyuki Takahashi, Hidekazu Takahashi, Makoto Ando, Takashi Murai, Akira Gomori, Zenjun Oda, Hidefumi Kitazawa, Yuko Mitobe, Maki Kanesaka, Tomoyuki Ohe, Hisashi Iwaasa, Yasuyuki Ishii, Akane Ishihara, Akio Kanatani, Takehiro Fukami. 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. Bioorganic & medicinal chemistry. 2009 Oct 1;17(19):6971-82