Organophosphorus-based (OP) nerve agents represent one of the most toxic, man-made chemicals ever assembled, and within the chemical warfare agent (CWA) arena, they are certainly the most feared due to their lethal efficiency and ease of large-scale production. Given the rapid toxicity observed after nerve agent exposure, a fast acting, efficacious therapeutic is needed to counteract these effects immediately after exposure. The current standard of care for nerve agent poisoning relies on the use of small molecule-based oximes that can efficiently restore acetylcholinesterase (AChE) activity. Despite their efficacy in reactivating AChE, the action of drugs like Pralidoxime(2-PAM) is strictly limited to the peripheral nervous system (PNS) and thus, provides no protection to the central nervous system (CNS). This lack of action in the CNS stems from the ionic nature of the drugs that prevents them from crossing the blood brain barrier (BBB) and thus access any nerve agent-inhibited AChE therein. The current challenge lies in developing neutral (hydrophobic) oximes that not only cross the BBB but are efficacious enough to reactivate inhibited AChE in both the PNS and CNS. The work described herein uses an iterative cycle involving parallel efforts in synthetic chemistry, computation, in vitroand in vivocapabilities. This cyclical approach seeks to balance the often competing aims of achieving BBB permeability and reactivation activity simultaneously. Using this approach, we have developed and characterized a new candidate oxime molecule LLNL-02 with superior BBB penetration, significant reactivation capacity and minimal toxicity in less than three years’ time.

Iterative approach for the development of a CNS-active oxime reactivator for nerve agent exposure

2019 Fall National Meeting

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