Refinement of Structural Leads for Centrally Acting Oxime Reactivators of Phosphylated Cholinesterases

Radić, Zoran; Sit, Rakesh K.; Kovarik, Zrinka; Berend, Suzana; Garcia, Edzna; Zhang, Limin; Amitai, Gabriel; Green, Carol; Radić, Božica; Fokin, Valery V.; Sharpless, K. Barry; Taylor, Palmer

doi:10.1074/jbc.m111.333732

Cited by 106 publications

(154 citation statements)

References 23 publications

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“…Although 2-PAM is an effective reactivator, one major deficiency is its inability to cross the blood-brain-barrier (BBB), thus preventing it from reactivating vital OP-inhibited AChE in the central nervous system (CNS). Over the last decade efforts have focused on screening and identifying other reactivating oximes that have a higher BBB permeability while still retaining a high reactivation profile (DeMar et al, 2010; García et al, 2010; Sit et al, 2011; Radic et al, 2012; Radic et al, 2013; Okolotowicz et al, 2014). In recent work by Radic et al, a promising centrally active oxime reactivator (RS194B, 4, Fig 1.)…”

Section: Introductionmentioning

confidence: 99%

The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

Malfatti

Enright

et al. 2017

Chemico-Biological Interactions

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Organophosphorus-based (OP) nerve agents represent some of the most toxic substances known to mankind. The current standard of care for exposure has changed very little in the past decades, and relies on a combination of atropine to block receptor activity and oxime-type acetylcholinesterase (AChE) reactivators to reverse the OP binding to AChE. Although these oximes can block the effects of nerve agents, their overall efficacy is reduced by their limited capacity to cross the blood-brain barrier (BBB). RS194B, a new oxime developed by Radic et al. (J. Biol. Chem., 2012) has shown promise for enhanced ability to cross the BBB. To fully assess the potential of this compound as an effective treatment for nerve agent poisoning, a comprehensive evaluation of its pharmacokinetic (PK) and biodistribution profiles was performed using both intravenous and intramuscular exposure routes. The ultra-sensitive technique of accelerator mass spectrometry was used to quantify the compound's PK profile, tissue distribution, and brain/plasma ratio at four dose concentrations in guinea pigs. PK analysis revealed a rapid distribution of the oxime with a plasma t1/2 of ∼1 hr. Kidney and liver had the highest concentrations per gram of tissue followed by lung, spleen, heart and brain for all dose concentrations tested. The Cmax in the brain ranged between 0.03-0.18% of the administered dose, and the brain-to-plasma ratio ranged from 0.04 at the 10 mg/kg dose to 0.18 at the 200 mg/kg dose demonstrating dose dependent differences in brain and plasma concentrations. In vitro studies show that both passive diffusion and active transport contribute little to RS194B traversal of the BBB. These results indicate that biodistribution is widespread, but very low quantities accumulate in the guinea pig brain, indicating this compound may not be suitable as a centrally active reactivator.

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Section: Introductionmentioning

confidence: 99%

The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

Malfatti

Enright

et al. 2017

Chemico-Biological Interactions

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“…The problem of delivering oxime antidotes to the brain has been addressed by many approaches so far. Several groups of researchers have tried to synthesise uncharged oximes that would be able to cross the blood-brain barrier (34)(35)(36)(37)(38), but these new classes of oximes fall short of pyridinium oxime efficiency when it comes to tabun reactivation (37,39). Much research has also been done to improve or modify transport of oximes across the blood-brain barrier.…”

Section: Figure 1 Rat Plasma and Tissue Concentrations Of K048 After mentioning

confidence: 99%

Translation of in vitro to in vivo pyridinium oxime potential in tabun poisoning / Translacija učinkovitosti piridinijevih oksima kod trovanja tabunom iz in vitro sustava u in vivo primjenu

Katalinić

Hrvat

Karasová

et al. 2015

Archives of Industrial Hygiene and Toxicology

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Even if organophosphorus (OP) nerve agents were banned entirely, their presence would remain a problem as weapons of terror (like in Syria). Oxime antidotes currently used in medical practice still fall short of their therapeutic purpose, as they fail to fully restore the activity of cholinesterases, the main target for OPs. As orphan drugs, these antidotes are tested too seldom for anybody's benefit. Over the last few decades, search for improved reactivators has reached new levels, but the translation of data obtained in vitro to in vivo application is still a problem that hinders efficient therapy. In this study, we tested the strengths and weaknesses of extrapolating pyridinium oxime antidotes reactivation efficiency from in vitro to in vivo application. Our results show that this extrapolation is possible with well-determined kinetic constants, but that it also largely depends on oxime circulation time and its tissue-specific distribution. This suggests that pharmacokinetic studies should be planned at the early stages of antidote development. Special attention should also be given to improving oxime distribution throughout the organism to overcome this major constraint in improving overall OP therapy.

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“…7,14 The previously described condensation of ethyl glyoxylate with hydroxylamine provided ethyl glyoxylate oxime (9). 15 The formation of an amide between ethyl glyoxylate oxime and an amine was reported in EtOH at 50 °C.…”

Section: Scheme 2 Synthesis Of 3-azido-1-phenyl-propylamine (5)mentioning

confidence: 99%

Enzyme-catalyzed cascade synthesis of hydroxyiminoacetamides

Knežević

Vinković

Maraković

et al. 2014

Tetrahedron Letters

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Refinement of Structural Leads for Centrally Acting Oxime Reactivators of Phosphylated Cholinesterases

Cited by 106 publications

References 23 publications

The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

Translation of in vitro to in vivo pyridinium oxime potential in tabun poisoning / Translacija učinkovitosti piridinijevih oksima kod trovanja tabunom iz in vitro sustava u in vivo primjenu

Enzyme-catalyzed cascade synthesis of hydroxyiminoacetamides

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