Ceetox analysis to de-risk drug development: The three antioxidants (NXY-059, radicut, and stazn)

Abstract

Translational stroke research is a multistep process where a drug candidate is synthesized, characterized using a series of in vitro assays and efficacy is then assessed in vivo in animal models representative of the clinical disease. Progress with the process is usually quite slow producing thousands to hundreds of thousands of candidates to screen. However, few candidates are ever fully developed into a randomized and double-blind clinical trial. To date, it is estimated that less than 40 small-molecule neuroprotective agents have been systematically studied in both preclinical and clinical trials, and those that have been tested in a randomized double-blind clinical trial have not proven to be positive. There are many points in the drug development process where a drug can fail to meet established criteria for further development. The critical points include lack of efficacy that could be established using a series of translational models for effective screening or toxicity that may be observed using in vitro or in vivo screening techniques. Since compound failure in the clinical situation is often attributed to toxicity, it is useful to introduce a de-risking step in the early preclinical development of novel small-molecule neuroprotective or neurotrophic compounds. This chapter reviews the CeeTox analysis panel that we have used in the development of small-molecule antioxidants such as NXY-059, Radicut, and STAZN.