Compositions and methods for reactivating cholinesterases
Inventors
Khavrutskii, Ilja • Wallqvist, Sven Anders
Assignees
Henry M Jackson Foundation for Advancedment of Military Medicine Inc • United States Department of the Army
Publication Number
US-11345653-B2
Publication Date
2022-05-31
Expiration Date
2037-06-16
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Abstract
The invention relates to compounds, compositions and methods for activating, reactivating, reversing or preventing the deactivation of cholinesterases, such as acetylcholinesterase and butyrylcholinesterase.
Core Innovation
The invention relates to compounds, compositions, and methods for activating, reactivating, reversing, or preventing the deactivation of cholinesterases, such as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The methods involve administering compounds of Formula I or pharmaceutically acceptable salts or prodrugs thereof to achieve these effects.
The problem being solved relates to the inactivation of AChE and BChE by organophosphorous compounds, which form covalent adducts with these enzymes leading to loss of function. This inactivation can result in severe toxicity, neurological damage, loss of muscle function, and death. Existing challenges include reactivating aged or non-aged inactivated cholinesterases and preventing the irreversible aging (dealkylation) of these enzymes.
Claims Coverage
The claims include two independent claims: one directed to a compound of Formula I, and another directed to a method of reactivating or preventing inactivation of acetylcholinesterase using such compounds.
Compound of Formula I
A compound defined by Formula I comprising a 5- or 6-membered substituted or unsubstituted aromatic, cycloalkyl, heteroaryl, or heterocyclic ring, with specified substituents (R1, R2, R3, etc.) having particular chemical groups and conditions such as at least one of R2 and R3 being NR11R12 with at least one of R11 and R12 being H.
Method for reactivating or preventing inactivation of acetylcholinesterase
Administering to a subject in need a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt to reactivate an inactivated acetylcholinesterase or prevent its inactivation.
The claims establish compounds defined by specific chemical structures and methods of using these compounds to reactivate or prevent inactivation of acetylcholinesterase, including aged enzyme forms and subject exposure to inactivating agents such as sarin, with possible co-administration of oximes.
Stated Advantages
The compounds are useful in reactivating both non-aged and aged inactivated acetylcholinesterase and butyrylcholinesterase, thereby potentially restoring enzyme function after organophosphate poisoning.
The compounds can prevent the irreversible aging (dealkylation) of cholinesterases, thus interfering with permanent inactivation.
Combination therapy with oximes may enhance treatment efficacy for exposure to nerve agents like sarin, soman, or cyclosarin.
Documented Applications
Treatment of toxicity associated with acetylcholinesterase inactivation in subjects exposed to inactivating agents, such as organophosphorous nerve toxins and pesticides.
Prevention of acetylcholinesterase and butyrylcholinesterase inactivation through prophylactic administration prior to the appearance of symptoms.
Reactivation of inactivated or aged cholinesterases in subjects suffering from effects of exposure to chemical nerve agents.
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