SAR and species/stereo-selective metabolism of the sorbitol dehydrogenase inhibitor, CP-470,711

Bioorg Med Chem Lett. 2002 Jun 3;12(11):1477-80. doi: 10.1016/s0960-894x(02)00208-1.

Abstract

SAR studies on the stereoisomers of CP-470,711 suggested that in vivo epimerization was taking place in rats. Further metabolism studies revealed that no epimerization was occurring in dogs, and that no epimerization was expected in humans. A mechanism for the in vivo epimerization is proposed involving an oxidation-reduction pathway of the secondary benzylic alcohol, in contrast to an acid/base-promoted epimerization of the same center during chemical synthesis.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Animals
  • Dogs
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Hepatocytes / enzymology
  • Humans
  • L-Iditol 2-Dehydrogenase / antagonists & inhibitors*
  • L-Iditol 2-Dehydrogenase / blood
  • L-Iditol 2-Dehydrogenase / chemical synthesis
  • L-Iditol 2-Dehydrogenase / metabolism*
  • Oxidation-Reduction
  • Pyrimidines / chemistry
  • Pyrimidines / metabolism*
  • Pyrimidines / pharmacology
  • Rats
  • Species Specificity
  • Stereoisomerism
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • CP-470711
  • Enzyme Inhibitors
  • Pyrimidines
  • L-Iditol 2-Dehydrogenase