Abstract
Acetylcholinesterase (AChE) reactivators (oximes) are compounds predominantly targeting the active site of the enzyme. Toxic effects of organophosphates nerve agents (OPNAs) are primarily related to their covalent binding to AChE and butyrylcholinesterase (BChE), critical detoxification enzymes in the blood and in the central nervous system (CNS). After exposure to OPNAs, accumulation of acetylcholine (ACh) overstimulates receptors and blocks neuromuscular junction transmission resulting in CNS toxicity. Current efforts at treatments for OPNA exposure are focused on non-quaternary reactivators, monoisonitrosoacetone oximes (MINA), and diacylmonoxime reactivators (DAM). However, so far only quaternary oximes have been approved for use in cases of OPNA intoxication. Five acetylcholinesterase reactivator candidates (K027, K075, K127, K203, K282) are presented here, together with pharmacokinetic data (plasma concentration, human serum albumin binding potency). Pharmacokinetic curves based on intramuscular application of the tested compounds are given, with binding information and an evaluation of structural relationships. Human Serum Albumin (HSA) binding studies have not yet been performed on any acetylcholinesterase reactivators, and correlations between structure, concentration curves and binding are vital for further development. HSA bindings of the tested compounds were 1% (HI-6), 7% (obidoxime), 6% (trimedoxime), and 5%, 10%, 4%, 15%, and 12% for K027, K075, K127, K203, and K282, respectively.
Highlights
Drug development is challenging work with numerous unknown variables that have to be taken into account, including the detailed pharmacokinetics of novel compounds [1]
Our work focuses on the pharmacokinetic properties of antidotes for irreversible AChE inhibitors that act directly on the cholinergic system and lead to hyperactivation of the choline system with all accompanying negative symptoms, e.g., bradycardia, hypotension, hypersecretion, bronchoconstriction, GI tract hypermotility, which, if left untreated, lead to death [18]
HI-6 is the only available oxime so far to show some efficacy against soman intoxication [32]
Summary
Drug development is challenging work with numerous unknown variables that have to be taken into account, including the detailed pharmacokinetics of novel compounds [1]. We present in vitro and in vivo determinations of plasma concentration and human serum albumin (HSA) binding potency of newly synthesized acetylcholinesterase (AChE, E.C. 3.1.1.7) reactivators. Properties of absorption, distribution, metabolism and excretion (“ADME”) are critical for determining the future potency of compounds in clinical practice. Quantifies the properties that compounds should possess to be eligible for success [2,3]. This rule postulates that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular weight is greater than 500 and the calculated Log P is greater than 5. Lipinsky et al (1997) [2] stated these properties for drug candidates to be used orally, it can be more or less applied to all drug formulations with appropriate modifications
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