Therapeutic Potential of the Lazaroids (21-Aminosteroids) in Acute Central Nervous System Trauma, Ischemia and Subarachnoid Hemorrhage

The chapter reviews the pharmacological properties of a novel series of lipid peroxidation (LP) inhibitors, the 21-aminosteroids that have been shown to be protective in experimental models of acute spinal cord or head injury, focal and global cerebral ischemia, and SAH. These compounds were developed subsequent to extensive studies concerning the ability of high doses of the glucocorticoid steroid, methylprednisolone (MP), to inhibit post-traumatic central nervous system (CNS) LP, an action unrelated to glucocorticoid receptor activation. The 21-aminosteroids were designed to be devoid of glucocorticoid receptor interactions while at the same time retaining a propensity for cell membrane localization and having improvements in LP inhibitory efficacy in comparison to MP. One of these compounds, U-7400SF, was selected for clinical development as a parenterally administered acute neuroprotective agent, and is currently the focus of phase III clinical trials in head and spinal cord injury, ischemic stroke, and aneurysmal SAH. The chapter provides a description of the mechanisms by which this compound inhibits LP, its efficacy in preclinical models, and results to date from phase I and II clinical trials.