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

J Med Chem. 2002 Sep 26;45(20):4398-401. doi: 10.1021/jm020288y.

Abstract

We report here a novel sorbitol dehydrogenase inhibitor, 16, that shows very high oral potency (50 microg/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.

MeSH terms

  • Administration, Oral
  • Animals
  • Caco-2 Cells
  • Diabetes Mellitus / metabolism
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Fructose / metabolism
  • Humans
  • L-Iditol 2-Dehydrogenase / antagonists & inhibitors*
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Rats
  • Sciatic Nerve / drug effects
  • Sciatic Nerve / metabolism
  • Solubility
  • Stereoisomerism
  • Structure-Activity Relationship
  • Triazines / chemical synthesis*
  • Triazines / chemistry
  • Triazines / pharmacology

Substances

  • 1-(4-(4-(4,6-dimethyl(1,3,5)triazin-2-yl)2,6,-dimethylpiperazin-1-yl)pyrimidin-2-yl)ethanol
  • Enzyme Inhibitors
  • Pyrimidines
  • Triazines
  • Fructose
  • L-Iditol 2-Dehydrogenase