Identification of Novel Brain-penetrating Phenoxyalkyl Pyridinium Oxime Countermeasures

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7. Project Summary/Abstract Many of the organophosphate (OP) anticholinesterases are highly toxic and have been developed as either nerve agents or insecticides. Prolonged acetylcholinesterase (AChE) inhibition results in glutamate-induced seizures with subsequent permanent brain damage. Some OPs are relatively easy to synthesize and could become threat agents of great concern from potential terrorist action where the specific OP employed might not be immediately known. Terrorist actions or accidents could lead to mass casualties in adults and children of both sexes. The current therapy consists of the muscarinic receptor antagonist atropine and an oxime reactivator of the inhibited AChE (2-PAM in the US). However 2-PAM is not broad-spectrum and cannot effectively penetrate the blood brain barrier, so it would leave victims poorly protected against some OP chemistries and would not attenuate the hypercholinergic activity in the brain and resultant brain damage. Therefore an improved oxime therapeutic is needed which can counteract both nerve agent and insecticidal chemistries and can restore brain cholinergic function to attenuate or prevent long-term central nervous system damage, so that both life and brain function may be preserved. Our laboratories have invented and patented (US Patent 9,277,937) a platform of substituted phenoxyalkyl pyridinium oximes that have shown broader based survival efficacy than 2-PAM and also attenuation of signs of seizure-like behavior and neuropathology in male rats exposed to high levels of both nerve agent and insecticidal chemistries. Limited studies in male guinea pigs against sarin have also showed efficacy. Only limited preliminary information exists at present with respect to the novel oximes' pharmacokinetics and no information exists on their therapeutic efficacy in female or juvenile animals. Preliminary data indicate that combinations of a novel oxime and 2-PAM are more efficacious than the single oximes. A combination of these two or combinations of two novel oximes with different specificities for nerve agent and insecticidal chemistries could provide a broader spectrum of efficacy than single oximes and provide a more effective therapeutic in the event of mass casualties induced by an unidentified OP. Therefore this application proposes the generation of additional efficacy data against a highly relevant sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP) and paraoxon (PXN; the active metabolite of the insecticide parathion) in adult female and juvenile (both sexes) rats, on our three most efficacious novel oximes and combinations of two oximes. Initial pharmacokinetic and initial oxime toxicity data will be generated. Lastly efficacy tests will be performed in male and female adult guinea pigs with sarin and VX. The goal of this Lead Identification project is to down-select to a lead and an alternate novel oxime or novel oxime binary combination that will be ready to enter into optimization studies through a subsequent Lead Optimization U01 project, that will move the novel oximes into advanced development toward FDA approval.