Separation of alpha-glucosidase-inhibitory and liver X receptor-antagonistic activities of phenethylphenyl phthalimide analogs and generation of LXRalpha-selective antagonists.

Liver X receptor (LXR) alpha/beta dual agonists are candidate medicaments for the treatment of metabolic syndrome, because their biological actions include increasing cholesterol efflux mediated by LXRbeta. However, their clinical application is currently limited by their enhancing effect on triglyceride (TG) synthesis mediated by LXRalpha. Combination of an LXRalpha-selective antagonist with an LXRalpha/beta dual agonist may overcome this disadvantage. In the present work, structural development studies of phenethylphenyl phthalimide 9, which possesses LXRalpha/beta dual-antagonistic activity and alpha-glucosidase-inhibitory activity, led to the LXRalpha-selective antagonist 23f. Specific alpha-glucosidase inhibitors were also obtained.