Optimization of Substituted Phenoxyalkyl Pyridinium Oximes as Therapies for Organophosphate Poisoning

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.

Grant Number: 5U01NS123255-05
NIH Institute/Center: NIH
Principal Investigator: Janice Chambers