Identification of novel and orally active spiroindoline NPY Y5 receptor antagonists.
A series of spiroindoline-3,4'-piperidine derivatives were synthesized and evaluated for their binding affinities and antagonistic activities at Y5 receptors. Potent Y5 antagonists were tested for their oral bioavailabilities and brain penetration in rats. Some of the antagonists showed good oral bioavailability and/or good brain penetration. In particular, compound 6e was orally bioavailable and brain penetrant, and oral administration of 6e inhibited bPP-induced food intake in rats with a minimum effective dose of 10mg/kg.
Sakamoto
Toshihiro
T
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba 300-2611, Japan.
Moriya
Minoru
M
Haga
Yuji
Y
Takahashi
Toshiyuki
T
Shibata
Takunobu
T
Okamoto
Osamu
O
Nonoshita
Katsumasa
K
Kitazawa
Hidefumi
H
Hidaka
Masayasu
M
Gomori
Akira
A
Iwaasa
Hisashi
H
Ishihara
Akane
A
Kanatani
Akio
A
Fukami
Takehiro
T
Gao
Ying-Duo
YD
Macneil
Douglas J
DJ
Yang
Lihu
L
D000284:Administration, Oral; D000588:Amines / Q000737:chemistry; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D007211:Indoles / Q000008:administration & dosage* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D017953:Isocyanates / Q000737:chemistry; D008956:Models, Chemical; D019151:Peptide Library; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D014508:Urea / Q000737:chemistry
D000588:Amines; D007211:Indoles; D017953:Isocyanates; D019151:Peptide Library; D017476:Receptors, Neuropeptide Y; C100568:neuropeptide Y5 receptor; C057812:indoline; D014508:Urea