(9S)-9-(2-hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one, a selective and orally active neuropeptide Y Y5 receptor antagonist.
(9S)-9-(2-Hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one ((S)-1) was identified as a selective and orally active neuropeptide Y Y5 receptor antagonist. The structure-activity relationship for this structural class was investigated and showed that limited substitution on the phenyl ring was tolerated and that modification of the 4,4-dimethyl group of the cyclohexenone and the 3,3-dimethyl group of the xanthenone parts slightly improved potency. The plasma concentration-time profile after oral administration of (S)-1 in Sprague-Dawley (SD) rats showed significant in vivo racemization of (S)-1 and that (S)-1 is cleared much more quickly than (R)-1. The duration of (S)-1 in SD rats after oral administration of (RS)-1 racemate was twice as long as that following oral administration of (S)-1. The C max values of (S)-1 after administration of (S)-1 and (RS)-1 were comparable, and the brain to plasma ratio for (S)-1 was 0.34 in SD rats. In our acute D-Trp (34)NPY-induced food intake model, both (S)-1 and (RS)-1 showed potent and dose-dependent efficacy. Therefore, the use of (RS)-1 is suitable for studies that require sustained plasma exposure of (S)-1.
Sato
Nagaaki
N
Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co, Ltd, Okubo 3, Tsukuba 300-2611, Japan. nagaaki_sato@merck.com
Jitsuoka
Makoto
M
Shibata
Takunobu
T
Hirohashi
Tomoko
T
Nonoshita
Katsumasa
K
Moriya
Minoru
M
Haga
Yuji
Y
Sakuraba
Aya
A
Ando
Makoto
M
Ohe
Tomoyuki
T
Iwaasa
Hisashi
H
Gomori
Akira
A
Ishihara
Akane
A
Kanatani
Akio
A
Fukami
Takehiro
T
D000284:Administration, Oral; D000821:Animal Feed; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002460:Cell Line; D003512:Cyclohexanones / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014966:Xanthenes / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
C531196:9-(2-hydroxy-4,4,-dimethyl-6-oxo-1-cyclohexen-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one; D003512:Cyclohexanones; D017476:Receptors, Neuropeptide Y; D014966:Xanthenes; C100568:neuropeptide Y5 receptor