Probe and Pharmaceutical Optimization Core (PPOC)

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Project Summary – Probe and Pharmaceutical Optimization Core (PPOC) – Core B The overall goal of the UC Davis CounterACT Center of Excellence is to identify and advance improved medical countermeasures for stopping seizures and preventing long-term consequences resulting from acute intoxication with chemical threat agents, specifically organophosphate cholinesterase inhibitors like diisopropylfluorophosphate (DFP), paraoxon and soman, or GABAA receptor blockers like tetramethylene- disulfotetramine (TETS), picrotoxin and bicuculline. The role of Core B, the Probe and Pharmaceutical Optimization Core, is to promote the overall Center goal by providing general medicinal chemistry, formulation and pharmacology support. Core B will function as an integral component of the Center by supporting Projects 1, 2 and 3, and by closely collaborating with Core A, the Analytical Chemistry Core. Core B will synthesize the chemical threat agent tetramethylenedisulfotetramine (TETS) and specific mechanistic probes for the individual projects, including TETS-haptens and analogs for the development of a TETS detection assay in Core A. Core B will further use its medicinal chemistry expertise to synthesize and characterize potential novel therapeutics, including soluble epoxide hydrolase (sEH) inhibitors, dual sEH/cyclooxygenase-2 (COX-2) or sEH/phosphodiesterase inhibitors, activators of small-conductance calcium- activated potassium channels (KCa2), blockers of the microglial voltage-gated potassium channel Kv1.3, as well as AMPA, ryanodine or GABA receptor antagonists, as required by the projects. Having a core dedicated to probe and reagent design, synthesis and/or verification will help ensure consistency, efficacy and reproducibility across the projects of the UC Davis Center and the CounterACT program. In contrast to the first project period, where the emphasis was on delivering libraries of diverse compounds for in vitro screening, the emphasis now will be on optimizing previously identified leads and candidate therapeutics for bioavailability, half-life and central nervous system (CNS) penetration. Core B will further devote significant effort to performing rapid efficacy and safety screens of candidate therapeutics and therapeutic combinations to help inform compound-combinations and dose- selection for Projects 2 and 3.