Synthesis of water-soluble prodrugs of BMS-191011: a maxi-K channel opener targeted for post-stroke neuroprotection

Bioorg Med Chem Lett. 2003 May 19;13(10):1695-8. doi: 10.1016/s0960-894x(03)00296-8.

Abstract

A variety of water-soluble prodrugs of BMS-191011 was synthesized and evaluated for solution state stability and rate of conversion to BMS-191011 in rat and human plasma. The deoxycarnitine ester prodrug (11c) was selected for clinical evaluation based on its superior chemical stability, crystallinity and cleavage to BMS-191011 in human plasma.

MeSH terms

  • Animals
  • Betaine / analogs & derivatives*
  • Blood / metabolism
  • Carnitine*
  • Crystallization
  • Dose-Response Relationship, Drug
  • Drug Stability
  • Heterocyclic Compounds, 3-Ring / chemical synthesis*
  • Heterocyclic Compounds, 3-Ring / metabolism
  • Heterocyclic Compounds, 3-Ring / pharmacokinetics
  • Humans
  • Neuroprotective Agents / chemical synthesis*
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacokinetics*
  • Oxadiazoles
  • Potassium Channels / agonists*
  • Prodrugs / chemical synthesis*
  • Prodrugs / metabolism*
  • Prodrugs / pharmacokinetics
  • Rats
  • Solubility
  • Stroke / drug therapy*
  • Structure-Activity Relationship
  • Water

Substances

  • 3-((5-chloro-2-hydroxyphenyl)methyl)-5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2(3H)-one
  • Heterocyclic Compounds, 3-Ring
  • Neuroprotective Agents
  • Oxadiazoles
  • Potassium Channels
  • Prodrugs
  • Water
  • Betaine
  • gamma-butyrobetaine
  • Carnitine