The Potential Development Sulfonylhydrazines for the Treatment of Alzheimer’s Disease

Abstract

The anticancer drug BCNU has striking activity against Alzheimer’s disease in humans. This activity is likely due to one of the many reactive electrophiles generated by BCNU. The structure and complex decomposition pathways of BCNU do not allow for the synthesis of analogs that can selectively generate these electrophiles. Therefore, their contributions to the anti-Alzheimer’s efficacy and toxicity of these different electrophiles cannot be determined. The sulfonylhydrazine prodrugs (SHP), which readily cross the blood-brain barrier, can be regarded as functional homologs of BCNU but with substantial design flexibility and tolerance for structural modification. Agents have been synthesized, which generate individual or combinations of identical or similar electrophiles to the electrophilic species produced by the BCNU. This should allow for the determination of which electrophilic species are important in the anti-Alzheimer’s disease activity and how using SHPs, we can generate the most efficacious of these electrophiles, in a more selective and less toxic manner, to generate an improved anti-Alzheimer’s agent.