CNS Active, Orally Bioavailable, Zwitterionic Oxime Antidotes to Organophosphates
Abstract
The proposed work is directed to advancing zwitterionic oximes as superior antidotes to nerve agent organophosphates used in chemical warfare and associated terrorism. Through structure guided antidote design involving mechanistic and structural studies and parallel pharmacokinetic analyses in rodents and non-human primates, we propose to complete the pre-IND phases of an Investigational New Drug application (IND) with the Food and Drug Administration (FDA) in 34 years with 1-2 years of refinement for safety and optimizing efficacy. Our lead zwitterionic oxime, RS 194B, is backed with second generation congeners should later stage, idiosyncratic or side reactions occur. Synthetic scale-up and corresponding pharmacological and analytical studies will be conducted at the University of California, San Diego (UCSD) and neighboring Scripps Research Institute. Efficacy and toxicity studies in mice after sarin vapor exposure will be conducted at the Institute for Medical Research and Occupational Health in Zagreb, Croatia with blood and tissue samples sent to UCSD for high resolution LC-MS/MS analysis. Similar arrangements for non-human primates (macaques) for studies at the Battelle Laboratories in Ohio with blood and occasional tissue samples sent to UCSD. Our proposed studies in La Jolla and Zagreb involve investigators that have collaborated for over a decade on cholinesterase structure, inhibition and reactivation by antidotes. Recent studies with the Battelle Institute involve in vivo studies in macaques are proposed for continuation and expansion in order to develop a dosing scheme to minimize oxime antidote toxicity and maximize efficacy as specified by the FDA Animal Rule. We also project studies to minimize renal clearance and brain efflux for RS 194B.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 01, 2019
- Source ID
- HDTRA11910006
Entities
People
- Palmer W. Taylor
Organizations
- Defense Threat Reduction Agency
- University of California, San Diego