ABSTRACT This project's primary endpoint focus will be efficiently rescuing toxic cyanide exposure using three distinct animal models. None of the current countermeasure options meet the requirements for the risk scenarios and objectives in PAR 22-209. There are continual threats of chemical exposure to human populations. Health and safety measures in the workplace cannot fully mitigate the chances of unexpected or malicious use of chemical toxicants. Safe and effective countermeasures to a cyanide chemical exposures that can deploy in a variety of challenging emergency settings represent a continual unmet medical need. In addition to survival, mitigating the sequel morbidities of toxic chemical exposures means another challenge for next-generation countermeasures. For metabolic poisons that reach high levels of exposure like cyanide, approaches to reverse the insult's effects are warranted to mitigate more prolonged-term effects. A team of investigators with experience in discovering and developing countermeasures and therapeutic agents and expertise in medicinal chemistry, pharmacology, toxicology, discovery pharmaceutics, in vivo phenotypic screens, and complimentary animal models will pursue milestones established from 3 specific aims. Aim 1: To improve and down-select next-generation platinum (II)- based countermeasure agents hydrogen cyanide scavengers with properties that meet the criteria for developability. Aim 2: To evaluate combinations of the metabolite glyoxylate with platinum (II)-based scavenger agents. Aim 3: To evaluate the efficacy and safety in a porcine model for cyanide intoxication of lead candidate platinum (II)-based agents alone and in combinations with the metabolite glyoxylate.