Preclinical Studies of Noncharged Oxime Reactivators for Organophosphate Exposure

ABSTRACT 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 am...

Full description

Saved in:
Bibliographic Details
Published inJournal of biochemical and molecular toxicology Vol. 28; no. 1; pp. 23 - 31
Main Authors Okolotowicz, Karl J., Dwyer, Mary, Smith, Emily, Cashman, John R.
Format Journal Article
LanguageEnglish
Published United States Blackwell Publishing Ltd 01.01.2014
Wiley Subscription Services, Inc
Subjects
Amidine-oxime reactivators
Animals
Biochemistry
Blood-Brain Barrier
Brain - drug effects
Brain - enzymology
Cholinesterase Inhibitors - toxicity
Cholinesterase Reactivators - pharmacokinetics
Cholinesterase Reactivators - pharmacology
Cholinesterases
HEK293 Cells
Humans
Male
Mice
Mice, Inbred BALB C
Microsomes, Liver - drug effects
Microsomes, Liver - enzymology
Organophosphate
Organophosphates - toxicity
Oximes
Oximes - pharmacokinetics
Oximes - pharmacology
Pharmacokinetics
Rats
Rats, Sprague-Dawley
Reactivation
Oximes
Amidine-oxime reactivators
Reactivation
Organophosphate
Pharmacokinetics
Cholinesterases
Online AccessGet full text

Cover

More Information
Summary:ABSTRACT 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.
Bibliography:ArticleID:JBT21519
istex:368EAE653950565DABFE11A0AD2EFC2DE4E45C7A
Human BioMolecular Research Institute
ark:/67375/WNG-4FF78QWM-0
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ObjectType-Article-2
ObjectType-Feature-1
ISSN:1095-6670
1099-0461
DOI:10.1002/jbt.21519