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Preclinical Studies of Noncharged Oxime Reactivators for Organophosphate Exposure
Author(s) -
Okolotowicz Karl J.,
Dwyer Mary,
Smith Emily,
Cashman John R.
Publication year - 2014
Publication title -
journal of biochemical and molecular toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.526
H-Index - 58
eISSN - 1099-0461
pISSN - 1095-6670
DOI - 10.1002/jbt.21519
Subject(s) - oxime , chemistry , amidine , organophosphate , pharmacology , blood–brain barrier , in vivo , toxicity , stereochemistry , biochemistry , organic chemistry , central nervous system , medicine , biology , microbiology and biotechnology , pesticide , agronomy
A countermeasure that protects the brain from organophosphate toxicity is an unmet need. Few small molecule reactivators that can cross the blood brain barrier and reactivate brain acetyl cholinesterases have been reported. Herein, we describe preclinical investigations of a new class of amidine–oxime reactivator of cholinesterases with improved potency and blood brain barrier permeability. ( Z )‐ N ‐(( E )‐1‐(Dimethylamino)‐2‐(hydroxyimino)ethylidene)butan‐1‐aminium chloride, 1 , is zwitterionic at physiological pH but possesses increased oxime nucleophilicity because of the adjacent amidine functionality. The amidine–oximes reported herein were observed to be nontoxic (up to 200 mg/kg in vivo) and are chemically and metabolically stable. The results presented herein show that uncharged amidine–oxime reactivators such as 1 can penetrate the blood brain barrier in animals and protect from the toxicity of nerve agent model compounds.