ZK200775: A Phosphonate Quinoxalinedione AMPA Antagonist for Neuroprotection in Stroke and Trauma
Stroke and head trauma are worldwide public health problems and leading causes of death and disability in humans, yet, no adequate neuroprotective treatment is available for therapy. Glutamate antagonists are considered major drug candidates for neuroprotection in stroke and trauma. However, N-methy...
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Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 1998-09, Vol.95 (18), p.10960-10965 |
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description | Stroke and head trauma are worldwide public health problems and leading causes of death and disability in humans, yet, no adequate neuroprotective treatment is available for therapy. Glutamate antagonists are considered major drug candidates for neuroprotection in stroke and trauma. However, N-methyl-D-asparate antagonists failed clinical trials because of unacceptable side effects and short therapeutic time window. α -Amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) antagonists derived from the quinoxalinedione scaffold cannot be used in humans because of their insolubility and resulting renal toxicity. Therefore, achieving water solubility of quinoxalinediones without loss of selectivity and potency profiles becomes a major challenge for medicinal chemistry. One of the major tenets in the chemistry of glutamate antagonists is that the incorporation of phosphonate into the glutamate framework results in preferential N-methyl-D-aspartate antagonism. Therefore, synthesis of phosphonate derivatives of quinoxalinediones was not pursued because of a predicted loss of their selectivity toward AMPA. Here, we report that introduction of a methylphosphonate group into the quinoxalinedione skeleton leaves potency as AMPA antagonists and selectivity for the AMPA receptor unchanged and dramatically improves solubility. One such novel phosphonate quinoxalinedione derivative and competitive AMPA antagonist ZK200775 exhibited a surprisingly long therapeutic time window of >4 h after permanent occlusion of the middle cerebral artery in rats and was devoid of renal toxicity. Furthermore, delayed treatment with ZK200775 commencing 2 h after onset of reperfusion in transient middle cerebral artery occlusion resulted in a dramatic reduction of the infarct size. ZK200775 alleviated also both cortical and hippocampal damage induced by head trauma in the rat. These observations suggest that phosphonate quinoxalinedione-based AMPA antagonists may offer new prospects for treatment of stroke and trauma in humans. |
doi_str_mv | 10.1073/pnas.95.18.10960 |
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Glutamate antagonists are considered major drug candidates for neuroprotection in stroke and trauma. However, N-methyl-D-asparate antagonists failed clinical trials because of unacceptable side effects and short therapeutic time window. α -Amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) antagonists derived from the quinoxalinedione scaffold cannot be used in humans because of their insolubility and resulting renal toxicity. Therefore, achieving water solubility of quinoxalinediones without loss of selectivity and potency profiles becomes a major challenge for medicinal chemistry. One of the major tenets in the chemistry of glutamate antagonists is that the incorporation of phosphonate into the glutamate framework results in preferential N-methyl-D-aspartate antagonism. Therefore, synthesis of phosphonate derivatives of quinoxalinediones was not pursued because of a predicted loss of their selectivity toward AMPA. Here, we report that introduction of a methylphosphonate group into the quinoxalinedione skeleton leaves potency as AMPA antagonists and selectivity for the AMPA receptor unchanged and dramatically improves solubility. One such novel phosphonate quinoxalinedione derivative and competitive AMPA antagonist ZK200775 exhibited a surprisingly long therapeutic time window of >4 h after permanent occlusion of the middle cerebral artery in rats and was devoid of renal toxicity. Furthermore, delayed treatment with ZK200775 commencing 2 h after onset of reperfusion in transient middle cerebral artery occlusion resulted in a dramatic reduction of the infarct size. ZK200775 alleviated also both cortical and hippocampal damage induced by head trauma in the rat. These observations suggest that phosphonate quinoxalinedione-based AMPA antagonists may offer new prospects for treatment of stroke and trauma in humans.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.95.18.10960</identifier><identifier>PMID: 9724812</identifier><language>eng</language><publisher>United States: National Academy of Sciences of the United States of America</publisher><subject>alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - antagonists & inhibitors ; Animals ; Biological Sciences ; Brain damage ; Cells, Cultured ; Cerebrovascular Disorders - drug therapy ; Cerebrovascular Disorders - physiopathology ; Craniocerebral trauma ; Craniocerebral Trauma - drug therapy ; Craniocerebral Trauma - physiopathology ; Dosage ; Evoked Potentials - drug effects ; Excitatory Amino Acid Antagonists - therapeutic use ; Gerbillinae ; In Vitro Techniques ; Inhibitory concentration 50 ; Ischemia ; Mice ; Neurons ; Neuroprotective Agents - therapeutic use ; Organophosphonates - chemistry ; Organophosphonates - therapeutic use ; Pharmacology ; Quinoxalines - chemistry ; Quinoxalines - therapeutic use ; Radioligand Assay ; Rats ; Reperfusion ; Stroke ; Strokes ; Time windows</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 1998-09, Vol.95 (18), p.10960-10965</ispartof><rights>Copyright 1993-1998 National Academy of Sciences</rights><rights>Copyright National Academy of Sciences Sep 1, 1998</rights><rights>Copyright © 1998, The National Academy of Sciences 1998</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c591t-a0203c1fedb7168a39c400f1a4e857e0724b2556152d12eef1e8bd26c127d4243</citedby><cites>FETCH-LOGICAL-c591t-a0203c1fedb7168a39c400f1a4e857e0724b2556152d12eef1e8bd26c127d4243</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/95/18.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/45999$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/45999$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9724812$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Turski, Lechoslaw</creatorcontrib><creatorcontrib>Huth, Andreas</creatorcontrib><creatorcontrib>Sheardown, Malcolm</creatorcontrib><creatorcontrib>McDonald, Fiona</creatorcontrib><creatorcontrib>Neuhaus, Roland</creatorcontrib><creatorcontrib>Schneider, Herbert H.</creatorcontrib><creatorcontrib>Dirnagl, Ulrich</creatorcontrib><creatorcontrib>Wiegand, Frank</creatorcontrib><creatorcontrib>Jacobsen, Poul</creatorcontrib><creatorcontrib>Ottow, Eckhard</creatorcontrib><title>ZK200775: A Phosphonate Quinoxalinedione AMPA Antagonist for Neuroprotection in Stroke and Trauma</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Stroke and head trauma are worldwide public health problems and leading causes of death and disability in humans, yet, no adequate neuroprotective treatment is available for therapy. Glutamate antagonists are considered major drug candidates for neuroprotection in stroke and trauma. However, N-methyl-D-asparate antagonists failed clinical trials because of unacceptable side effects and short therapeutic time window. α -Amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) antagonists derived from the quinoxalinedione scaffold cannot be used in humans because of their insolubility and resulting renal toxicity. Therefore, achieving water solubility of quinoxalinediones without loss of selectivity and potency profiles becomes a major challenge for medicinal chemistry. One of the major tenets in the chemistry of glutamate antagonists is that the incorporation of phosphonate into the glutamate framework results in preferential N-methyl-D-aspartate antagonism. Therefore, synthesis of phosphonate derivatives of quinoxalinediones was not pursued because of a predicted loss of their selectivity toward AMPA. Here, we report that introduction of a methylphosphonate group into the quinoxalinedione skeleton leaves potency as AMPA antagonists and selectivity for the AMPA receptor unchanged and dramatically improves solubility. One such novel phosphonate quinoxalinedione derivative and competitive AMPA antagonist ZK200775 exhibited a surprisingly long therapeutic time window of >4 h after permanent occlusion of the middle cerebral artery in rats and was devoid of renal toxicity. Furthermore, delayed treatment with ZK200775 commencing 2 h after onset of reperfusion in transient middle cerebral artery occlusion resulted in a dramatic reduction of the infarct size. ZK200775 alleviated also both cortical and hippocampal damage induced by head trauma in the rat. 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Glutamate antagonists are considered major drug candidates for neuroprotection in stroke and trauma. However, N-methyl-D-asparate antagonists failed clinical trials because of unacceptable side effects and short therapeutic time window. α -Amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) antagonists derived from the quinoxalinedione scaffold cannot be used in humans because of their insolubility and resulting renal toxicity. Therefore, achieving water solubility of quinoxalinediones without loss of selectivity and potency profiles becomes a major challenge for medicinal chemistry. One of the major tenets in the chemistry of glutamate antagonists is that the incorporation of phosphonate into the glutamate framework results in preferential N-methyl-D-aspartate antagonism. Therefore, synthesis of phosphonate derivatives of quinoxalinediones was not pursued because of a predicted loss of their selectivity toward AMPA. Here, we report that introduction of a methylphosphonate group into the quinoxalinedione skeleton leaves potency as AMPA antagonists and selectivity for the AMPA receptor unchanged and dramatically improves solubility. One such novel phosphonate quinoxalinedione derivative and competitive AMPA antagonist ZK200775 exhibited a surprisingly long therapeutic time window of >4 h after permanent occlusion of the middle cerebral artery in rats and was devoid of renal toxicity. Furthermore, delayed treatment with ZK200775 commencing 2 h after onset of reperfusion in transient middle cerebral artery occlusion resulted in a dramatic reduction of the infarct size. ZK200775 alleviated also both cortical and hippocampal damage induced by head trauma in the rat. These observations suggest that phosphonate quinoxalinedione-based AMPA antagonists may offer new prospects for treatment of stroke and trauma in humans.</abstract><cop>United States</cop><pub>National Academy of Sciences of the United States of America</pub><pmid>9724812</pmid><doi>10.1073/pnas.95.18.10960</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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subjects | alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - antagonists & inhibitors Animals Biological Sciences Brain damage Cells, Cultured Cerebrovascular Disorders - drug therapy Cerebrovascular Disorders - physiopathology Craniocerebral trauma Craniocerebral Trauma - drug therapy Craniocerebral Trauma - physiopathology Dosage Evoked Potentials - drug effects Excitatory Amino Acid Antagonists - therapeutic use Gerbillinae In Vitro Techniques Inhibitory concentration 50 Ischemia Mice Neurons Neuroprotective Agents - therapeutic use Organophosphonates - chemistry Organophosphonates - therapeutic use Pharmacology Quinoxalines - chemistry Quinoxalines - therapeutic use Radioligand Assay Rats Reperfusion Stroke Strokes Time windows |
title | ZK200775: A Phosphonate Quinoxalinedione AMPA Antagonist for Neuroprotection in Stroke and Trauma |
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