Novel 21-aminosteroids that inhibit iron-dependent lipid peroxidation and protect against central nervous system trauma

J Med Chem. 1990 Apr;33(4):1145-51. doi: 10.1021/jm00166a010.

Abstract

A novel class of 21-aminosteroids has been developed. Compounds within this series are potent inhibitors of iron-dependent lipid peroxidation in rat brain homogenates with IC50's as low as 3 microM. Furthermore, selected members enhance early neurological recovery and survival in a mouse head injury model. Significant improvement in the 1 h post-head-injury neurological status (grip test score) by as much as 168.6% of the control has been observed. The most efficacious compound in this assay (30) showed an increase in the 1-week survival of 78.6% as compared to 27.3% for the vehicle-treated mice in the head-injury model. Based on its biological profile, 21-[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16 alpha- methylpregna-1,4,9(11)-triene-3,20-dione monomethanesulfonate (30) was selected for further evaluation and is currently entering phase I clinical trials for the treatment of head and spinal trauma.

MeSH terms

  • Amines / chemical synthesis*
  • Amines / pharmacology
  • Animals
  • Antioxidants / chemical synthesis*
  • Craniocerebral Trauma / drug therapy
  • Craniocerebral Trauma / metabolism
  • Drug Evaluation, Preclinical
  • Lipid Peroxidation / drug effects*
  • Male
  • Mice
  • Pregnatrienes / pharmacology*
  • Rats
  • Spinal Injuries / drug therapy
  • Steroids / chemical synthesis*
  • Steroids / pharmacology
  • Structure-Activity Relationship

Substances

  • Amines
  • Antioxidants
  • Pregnatrienes
  • Steroids
  • tirilazad