A Sorbitol Dehydrogenase Inhibitor of Exceptional in Vivo Potency with a Long Duration of Action:  1-(R)-{4-[4-(4,6-Dimethyl[1,3,5]triazin-2-yl)- 2R,6S-dimethylpiperazin-1-yl]pyrimidin-2- yl}ethanol

We report here a novel sorbitol dehydrogenase inhibitor, 16, that shows very high oral potency (50 mug/kg) in normalizing elevated fructose levels in the sciatic nerve of chronically diabetic rats and sustained duration of action (> 24 h). Furthermore, 16 shows attractive pharmaceutical properties, including good solubility in simulated human gastric fluid, excellent Caco-2 Papp, moderate lipophilicity, and metabolic stability for achieving good oral absorption and long duration of action.