(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

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

(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.

Original languageEnglish
Pages (from-to)4765-4770
Number of pages6
JournalJournal of Medicinal Chemistry
Volume51
Issue number15
DOIs
Publication statusPublished - 2008 Aug 14
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Sato, N., Jitsuoka, M., Shibata, T., Hirohashi, T., Nonoshita, K., Moriya, M., Haga, Y., Sakuraba, A., Ando, M., Ohe, T., Iwaasa, H., Gomori, A., Ishihara, A., Kanatani, A., & Fukami, T. (2008). (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. Journal of Medicinal Chemistry, 51(15), 4765-4770. https://doi.org/10.1021/jm8003587