Optimization of Substituted Phenoxyalkyl Pyridinium Oximes as Therapies for Organophosphate Poisoning

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7. Project Summary/Abstract Many of the organophosphate (OP) anticholinesterases, such as nerve agents, are highly toxic. Terrorist actions or accidents involving OPs could lead to mass casualties with potentially high levels of lethality. The current therapy consists of the muscarinic receptor antagonist atropine and an oxime reactivator of the inhibited acetylcholinesterase (2-PAM in the US). However, 2-PAM is not always effective at saving lives and cannot effectively penetrate the blood brain barrier, so 2-PAM can leave victims poorly protected. An improved oxime therapeutic is needed to counteract nerve agent lethality and assist with neuroprotection, so that both life and brain function may be preserved. Our laboratories have invented, patented and licensed a platform of substituted phenoxyalkyl pyridinium oximes that have shown better survival efficacy than 2-PAM and, unlike 2- PAM, attenuation of signs of seizure-like behavior and neuropathology in rats exposed to high levels of highly relevant nerve agent surrogates. Limited studies in male guinea pigs against sarin have also shown efficacy. With our current CounterACT Lead Identification U01 the efficacious compounds (the “actives”) have been down-selected to a lead and an alternate, with Oxime 20 being proposed as the Active Pharmaceutical Ingredient (API). The proposed project will build on the present survival efficacy, pharmacokinetic and API toxicity information in rats. Initially a superior vehicle for the API will be developed as a better solvent for the lipophilic API. A pharmacodynamic aim (Aim 1) will determine in rats (both sexes) whether a lower dosage of the API will be effective in promoting survival of lethal dosages of a sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP; a G agent chemistry) and a VX surrogate (nitrophenyl ethyl methylphosphonate, NEMP; a V agent chemistry) alone or in combination with 2-PAM. A pharmacokinetic (PK) aim (Aim 2) will determine the PK of the API in the new vehicle, plasma protein binding and hepatic microsomal metabolism in rats of both sexes and will introduce studies of a larger non-rodent test species, the Gottingen minipig, both sexes. An oxime toxicity aim (Aim 3) will investigate dose responses of the API for gross pathological, histopathological, clinical chemistry and hematology adverse results in rats and minipigs of both sexes to identify a Maximum Tolerated Dosage and a No Observed Adverse Effect Level, as well as in vitro genotoxicity and drug-drug interactions for CYPs and transporters. A chemistry aim (Aim 4) will support the previous 3 aims by providing the synthesis of NIMP, NEMP and the API, produce a new vehicle with improved solvent properties, evaluate API stability, and provide initial plans for manufacturing and Chemical Manufacturing Controls. All studies will be non-GLP and will follow FDA guidance from pre-IND meetings. The overarching goal of this Lead Optimization project is to provide optimized pharmacological and toxicological information on our lead oxime in both sexes of two species that will prepare the API to move into advanced development toward FDA approval.