Regulation of exercise ability and glycolipid metabolism by synthetic SR9009 analogues as new REV-ERB-α agonists.

ABSTRACT

SR9009 is an activator of REV-ERBs with diverse biological activities, including improving exercise tolerance and controlling skeletal muscle mass. To optimise the carbamate motif of SR9009, analogues of SR9009 were synthesised and evaluated. All of them showed REV-ERB-α agonist activities. Among them, 5a, 5f, 5 g, 5m, and 5p showed potencies equivalent to or slightly higher than the potency of SR9009 in vitro. These data indicate that the halogenated benzyl group is an indispensable active group in these compounds. 5m, 5p and SR9009 improved exercise tolerance in normal mice in vivo. Additionally, in hyperlipidemic mice, 5m and 5p not only improved exercise tolerance but also lowered blood lipid levels. 5m and 5p displayed stronger hypoglycaemic activity than SR9009.