The synthesis of novel adamantane-like cage compounds consisting of phosphorus, sulfur, and carbon atoms was developed. We examined the reaction of a variety of acetophenone derivatives with P4S10 in refluxing benzene. A novel noradamantane-like cage compound was also synthesized, when the reaction of 2'-methoxyacetophenone with P4S10 was performed in refluxing toluene. In addition, by using the adamantane-like cage compound, 4,4'dimethoxybenzophenone and N,N-dimethylbenzamide were successfully transformed into the corresponding thioketone (98%) and benzothioamide (89%), respectively.
Structurally diverse small compounds are utilized to obtain hit compounds that have suitable pharmacophores in appropriate three-dimensional conformations for the target drug receptors. We have focused on the 1,3,5-trioxazatriquinane skeleton, which has a high degree of three-dimensional properties, leading to a novel small-scale focused library based on 1,3,5- trioxazatriquinane. In the library screening for the orexin receptor, some of the compounds showed orexin receptor antagonistic activity with a high hit rate of 7%. By optimizing the hit compounds, we discovered a potent dual orexin receptor antagonist, 38b, and a selective orexin 1 receptor antagonist, 41b carrying the same plane structure. Both compounds showed reasonable brain permeability and beneficial effects when administered intraperitoneally to wild-type mice. Docking simulations of their eutomers, (–)-38b and (+)-41b, with orexin receptors suggested that the interaction between the 1,3,5-trioxazatriquinane core structure and the hydrophobic subpocket in orexin receptors enables a U-shape structure, which causes tight van der Waals interactions with the receptors similar to SB-334867, a selective orexin 1 receptor antagonist. These results indicate that the 1,3,5-trioxazatriquinanes bearing multiple effective residues (TriMERs) could serve as a privileged structure for G-protein coupled receptors (GPCRs) and the TriMER library approach might be useful for the hit discovery process targeting other GPCRs not only opioid and orexin receptors.
Structurally diverse small compounds are utilized to obtain hit compounds that have suitable pharmacophores in appropriate three-dimensional conformations for the target drug receptors. We have focused on the 1,3,5-trioxazatriquinane skeleton, which has a high degree of three-dimensional properties, leading to a novel small-scale focused library based on 1,3,5- trioxazatriquinane. In the library screening for the orexin receptor, some of the compounds showed orexin receptor antagonistic activity with a high hit rate of 7%. By optimizing the hit compounds, we discovered a potent dual orexin receptor antagonist, 38b, and a selective orexin 1 receptor antagonist, 41b carrying the same plane structure. Both compounds showed reasonable brain permeability and beneficial effects when administered intraperitoneally to wild-type mice. Docking simulations of their eutomers, (–)-38b and (+)-41b, with orexin receptors suggested that the interaction between the 1,3,5-trioxazatriquinane core structure and the hydrophobic subpocket in orexin receptors enables a U-shape structure, which causes tight van der Waals interactions with the receptors similar to SB-334867, a selective orexin 1 receptor antagonist. These results indicate that the 1,3,5-trioxazatriquinanes bearing multiple effective residues (TriMERs) could serve as a privileged structure for G-protein coupled receptors (GPCRs) and the TriMER library approach might be useful for the hit discovery process targeting other GPCRs not only opioid and orexin receptors.
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