Todd Zankel

Mercaptor’s prodrug platform restricts drug activity to areas of disease and injury in the CNS. Prodrug activation requires the unique environment found at such sites. Activation chemistry can be defined as limit oxidation of a prodrug thiol or disulfide to its sulfonic acid congener by pathogenically elevated ROS, catalyzed by unchaperoned, redox-active, transition metal ions (copper, iron). Levels of these species increase in proportion to the extent of pathology. Studies in living subjects demonstrated that prodrug activation occurs only in the CNS and only in extracellular environments enriched with ROS and free metals. These conditions are unique to the afflicted CNS due to the near absence of redox buffering in the extracellular space of the brain. The key physiological redox buffer, albumin, is present centrally at levels that are a small fraction of those found peripherally. Prodrug activation was undetectable in blood, CSF and healthy brain tissue for over 48 hours post-administration. In the same studies, an excitotoxic insult resulted in rapid, quantitative, prodrug conversion within the injured areas of the brain, reaching micromolar levels of active drug in minutes, while remaining below LOQ in blood and CSF. The prodrug modification also improves cBBB transit scores, a consequence of reduced polar surface area and increased log P. Our freshman candidate pool consists of well-documented therapeutics acting locally to enhance GABA and taurine activity or to antagonize P2Y12R, AGTR1, CD40L, SHP2, PIK3CB and S1PR1. Directed, rational, efforts will be able to access a much wider set of hits for subsequent development. Similarly, well-vetted SAR rules for the platform make artificial intelligence an attractive means of accessing greater areas of chemical space. Over a hundred years ago, Paul Ehrlich coined the term "magic bullet". Since then, this concept has been realized only imperfectly. With these prodrugs, we propose to have done so without compromise.