(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

Nagaaki Sato, Makoto Jitsuoka, Takunobu Shibata, Tomoko Hirohashi, Katsumasa Nonoshita, Minoru Moriya, Yuji Haga, Aya Sakuraba, Makoto Ando, Tomoyuki Ohe, Hisashi Iwaasa, Akira Gomori, Akane Ishihara, Akio Kanatani, Takehiro Fukami

研究成果: Article査読

46 被引用数 (Scopus)

抄録

(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 Cmax 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-Trp34NPY-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.

本文言語English
ページ(範囲)4765-4770
ページ数6
ジャーナルJournal of Medicinal Chemistry
51
15
DOI
出版ステータスPublished - 2008 8 14
外部発表はい

ASJC Scopus subject areas

  • 分子医療
  • 創薬

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「(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」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

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