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 Toxicoljournal_title
Journal of biochemical and molecular toxicologyauthors
Okolotowicz KJ,Dwyer M,Smith E,Cashman JRdoi
10.1002/jbt.21519subject
Has Abstractpub_date
2014-01-01 00:00:00pages
23-31issue
1eissn
1095-6670issn
1099-0461journal_volume
28pub_type
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