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In contrast to the inactive enantiomer S 50133, S 50131 lowered glycaemia in db/db mice in a dose-dependent manner, with significant activity reached at the concentration of 45?mg��kg?1 (P??0.05 after 6?h). S 51434 and its parent S 50612 lowered glycaemia with higher potency than S 50131 and S 49164, with significant activity still remaining 6?h after oral administration at 15?mg��kg?1 (P?[http://en.wikipedia.org/wiki/Temsirolimus Temsirolimus] an expected long-term antidiabetic efficacy. This was evaluated by measuring HbA1c levels after 4 weeks of daily oral administration in db/db mice (Figure?5A,G). Doses were adjusted in order to take into account the 1.5-fold higher relative hypoglycaemic potency of S 51434 observed after 4?h in acute conditions (Figure?4). Thus, S 50131 and S 51434 were given at 60 and 180?��mol��kg?1 (equivalent to 18.5 and 55.5?mg��kg?1) and 40 and 120?��mol��kg?1 (equivalent to 13.5 and 40.4?mg��kg?1), respectively. Safety was evaluated by measuring [http://www.selleckchem.com/screening/pfizer-licensed-library.html www.selleckchem.com] plasma FFA and TG levels, as well as the hepatic TG content at the end of the study. Both enantiomers were tested in parallel with 120?��mol��kg?1 N00236460 or GKA50 (equivalent [http://www.selleckchem.com/products/pifithrin-alpha.html Pifithrin��] to 46.2?mg��kg?1 or 55.8?mg��kg?1, respectively), two reference GKAs previously shown to have excellent in vivo efficacy in rodents (McKerrecher et?al., 2006; De Ceuninck et?al., 2013). These two GKAs were previously shown to decrease HbA1c levels while increasing hepatic TGs when evaluated in db/db mice (De Ceuninck et?al., 2013). In the present study, none of the GKAs tested altered glycaemia measured on days 14 and 28 (Supporting Information Figure?S1), most likely because their acute efficacy was no longer present at the time of sampling (21?h after administration). As expected, N00236460 and GKA50 significantly increased the hepatic TG content (P?