title: Amidine-oximes: reactivators for organophosphate exposure.
abstract: A new class of amidine-oxime reactivators of organophosphate (OP)-inhibited cholinesterases (ChE) were designed, synthesized, and tested. These compounds represent a novel group of oximes with enhanced capabilities of crossing the blood-brain barrier. Lack of brain penetration is a major limitation for currently used oximes as antidotes of OP poisoning. The concept described herein relies on a combination of an amidine residue and oxime functionality whereby the amidine increases the binding affinity to the ChE and the oxime is responsible for reactivation. Amidine-oximes were tested in vitro and reactivation rates for OP-BuChE were greater than pralidoxime (2-PAM) or monoisonitrosoacetone (MINA). Amidine-oxime reactivation rates for OP-AChE were lower compared to 2-PAM but greater compared with MINA. After pretreatment for 30 min with oximes 15c and 15d (145 μmol/kg, ip) mice were challenged with a soman model compound. In addition, 15d was tested in a post-treatment experiment (145 μmol/kg, ip, administration 5 min after sarin model compound exposure). In both cases, amidine-oximes afforded 100% 24 h survival in an animal model of OP exposure.
authors: Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, California 92121, United States. jkalisiak@hbri.org
authors: Jarosław
authors: J
authors: Kalisiak
authors: Erik C
authors: EC
authors: Ralph
authors: Jun
authors: J
authors: Zhang
authors: John R
authors: JR
authors: Cashman
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000506:poisoning; D002800:Cholinesterase Inhibitors / Q000506:poisoning*; D002802:Cholinesterases / Q000737:chemistry / Q000378:metabolism*; D004793:Enzyme Reactivators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D062025:Organophosphate Poisoning; D009943:Organophosphorus Compounds; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010539:Permeability; D011994:Recombinant Proteins / Q000737:chemistry; D012524:Sarin / Q000506:poisoning; D012999:Soman / Q000506:poisoning; D013329:Structure-Activity Relationship
chemical_list: C559867:2-(hydroxyimino)-N,N-dimethyl-N'-propylacetimidamide; D000578:Amidines; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D004793:Enzyme Reactivators; C559866:N'-ethyl-2-(hydroxyimino)-N,N-dimethylacetimidamide; D009943:Organophosphorus Compounds; D010091:Oximes; D011994:Recombinant Proteins; D012999:Soman; D012524:Sarin; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002802:Cholinesterases; C053914:cyclohexyl methylphosphonofluoridate