Preclinical studies of noncharged oxime reactivators for organophosphate exposure.
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.
Human BioMolecular Research Institute, San Diego, CA, 92121, USA. kokolotowicz@hbri.org.
Karl J
KJ
Okolotowicz
Mary
M
Dwyer
Emily
E
Smith
John R
JR
Cashman
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000493:pharmacokinetics / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010755:Organophosphates / Q000633:toxicity*; D010091:Oximes / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010755:Organophosphates; D010091:Oximes
Amidine-oxime reactivators; Cholinesterases; Organophosphate; Oximes; Pharmacokinetics; Reactivation