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 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.

journal_name

J Biochem Mol Toxicol

authors

Okolotowicz KJ,Dwyer M,Smith E,Cashman JR

doi

10.1002/jbt.21519

subject

Has Abstract

pub_date

2014-01-01 00:00:00

pages

23-31

issue

1

eissn

1095-6670

issn

1099-0461

journal_volume

28

pub_type

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