(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

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 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.

Sulfamic acid-catalyzed, environmentally benign synthesis of bis-tetronic acids at ambient temperature

“…1B) result from the reaction between the same diketones with aromatic aldehydes, devoid of the ortho-hydroxyl group [21][22][23][24]. Among these, 1-oxo-hexahydroxanthenes are known for their important pharmacological properties, such as anti-estrogenic, antimicrobial, hypoglycaemic, antibacterial and thrombin inhibitory activities and serve as neuropeptide YY5 receptor antagonists [25][26][27][28], while tetraketones are known to possess antitumor activity [29][30][31][32]. On the other hand, bis-coumarins (Fig.…”

Facile construction of 3-indolochromenes and 3-indoloxanthenes via EDDF catalyzed one-pot three component reactions

“…MCRs with their inherent advantages viz. [7][8][9][10] Union of these biologically relevant scaffolds is likely to produce more active compounds and recently, the synthesis of 3-substituted indolo-pyrans via the one-pot MCR between salicylaldehyde, an active methylene compound (malononitrile/1,3-dicarbonyls), and indole utilizing a tandem Knoevenagel-Pinner-cyclization-Friedel-Crafts sequence, has gained much attention. 2,3 Indole is considered as a privileged scaffold for drug discovery, 4,5 as this electron-rich hetero-aromatic fragment is found to possess many important biological functions.…”

Novel orally active NPY Y5 receptor antagonists: Synthesis and structure–activity relationship of spiroindoline class compounds

“…To date, various structurally diverse NPY Y5 receptor antagonists have been reported by a number of research groups, including ours. [10][11][12][13][14][15][16][17][18][19][20][21][22][23] Previously, our group reported several types of Y5 antagonists. [18][19][20][21][22][23] Our first lead compound, 1, was designed following similarity searching of an MRL compound collection, and had very high potency against Y5 receptor (IC 50 : 0.85 nM).…”