title: 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.
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 1mg/kg. This compound was selected for proof-of-concept studies in human clinical trials.
authors.affiliation: Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba 300-2611, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Haga
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Takunobu
authors.initials: T
authors.lastname: Shibata
authors.forename: Katsumasa
authors.initials: K
authors.lastname: Nonoshita
authors.forename: Makoto
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Takuya
authors.initials: T
authors.lastname: Suga
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takahashi
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Takahashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Ando
authors.forename: Takashi
authors.initials: T
authors.lastname: Murai
authors.forename: Akira
authors.initials: A
authors.lastname: Gomori
authors.forename: Zenjun
authors.initials: Z
authors.lastname: Oda
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Kitazawa
authors.forename: Yuko
authors.initials: Y
authors.lastname: Mitobe
authors.forename: Maki
authors.initials: M
authors.lastname: Kanesaka
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ohe
authors.forename: Hisashi
authors.initials: H
authors.lastname: Iwaasa
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ishii
authors.forename: Akane
authors.initials: A
authors.lastname: Ishihara
authors.forename: Akio
authors.initials: A
authors.lastname: Kanatani
authors.forename: Takehiro
authors.initials: T
authors.lastname: Fukami
mesh_terms: 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
chemical_list: D018528:ATP-Binding Cassette Transporters; D000577:Amides; D001572:Benzofurans; D017476:Receptors, Neuropeptide Y; D013141:Spiro Compounds; C100568:neuropeptide Y5 receptor; C105430:benzofuran