Pharmaceutical Sciences Core

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Abstract: The goal of the Pharmaceutical Sciences Core (PSC) is to provide drug development capabilities needed by the Center to enable the rapid translation of new chemical entities (NCEs) useful for cyanide countermeasures. The approach will be to add both capacity and capabilities in pharmacokinetics, toxicology, medicinal chemistry, and formulation through a collaborative team lead by Drs. V. J. Davisson and Gregory Knipp at Purdue University. The U54 program currently is able to use unbiased screening approaches in zebrafish to identify new chemical entities that show protection against cyanide toxicities. From the programs, there is capacity to conduct hit follow-up chemistry to qualification of new hit chemotypes. The PSC will critically evaluate and prioritize lead candidate compounds and formulations while executing hit-to-lead development studies. A focus of the U54 program moving forward is to establish, in addition to traditional scavengers, new metabolic modulators for tissue and organ protection against cyanide toxicity. While feasibility for translation to animal models is being demonstrated with hit compounds, barriers in meeting the product concept for relevant threat scenarios are significant. The PSC will provide capabilities for standardized in vivo pharmacology and toxicology support, pharmacokinetic assessment, physicochemical and solid-state property assessment and selection, preclinical formulation support that will accelerate translation and fulfill the program deliverables. A lead candidate staging process will be implemented to a) improve processes for assessment of the hit-to-leads and interface with in vivo models, b) improve the capacity to select compounds for lead development from the discovery group, c) provide entrée to lead compound efficacy and safety evaluation in mammalian models. In doing so, the PSC will impact decision making and resource management to enhance pharmaceutical strategies (developability properties) to enable more efficient transition from zebrafish to mammals.