Source:http://linkedlifedata.com/resource/pubmed/id/10780908
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
8
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pubmed:dateCreated |
2000-5-11
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pubmed:abstractText |
AMP deaminase (AMPDA) inhibitors increase the levels of extracellular adenosine and preserve intracellular adenylate pools in cellular models of ATP depletion and therefore represent a potential new class of antiischemic drugs. Recently we reported that replacement of the ribose 5'-monophosphate component of the very potent transition-state analogue AMPDA inhibitor coformycin monophosphate (1) with a simple alkylcarboxy group resulted in potent, selective, and cell-penetrating AMPDA inhibitors. Here we report that replacement of this alkylcarboxy group with an alpha-substituted alkylmalonic acid resulted in enhanced inhibitor potency. The lead compound, 3-(5, 5-dicarboxy-6-(3-(trifluoromethyl)phenyl)-n-hexyl)coformycin aglycon (21), exhibited an AMPDA K(i) of 0.029 microM which is (3 x 10(5))-fold lower than the K(M) for the natural substrate AMP. A comparison of inhibitory potencies shows that the diacid analogues with alpha-benzyl substituents are 2-10-fold more inhibitory than similar monoacid-monoester, monoester-monoamide, or diester derivatives. Finally, these diacid analogues are 2-40-fold more potent inhibitors than the corresponding monocarboxylates.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/AMP Deaminase,
http://linkedlifedata.com/resource/pubmed/chemical/Coformycin,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Malonates,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphoric Acid Esters,
http://linkedlifedata.com/resource/pubmed/chemical/Ribose
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0022-2623
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
20
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pubmed:volume |
43
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1519-24
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pubmed:dateRevised |
2002-11-8
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pubmed:meshHeading |
pubmed-meshheading:10780908-AMP Deaminase,
pubmed-meshheading:10780908-Binding Sites,
pubmed-meshheading:10780908-Coformycin,
pubmed-meshheading:10780908-Enzyme Inhibitors,
pubmed-meshheading:10780908-Malonates,
pubmed-meshheading:10780908-Molecular Mimicry,
pubmed-meshheading:10780908-Phosphoric Acid Esters,
pubmed-meshheading:10780908-Ribose,
pubmed-meshheading:10780908-Structure-Activity Relationship
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pubmed:year |
2000
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pubmed:articleTitle |
AMP deaminase inhibitors. 4. Further N3-substituted coformycin aglycon analogues: N3-alkylmalonates as ribose 5'-monophosphate mimetics.
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pubmed:affiliation |
Metabasis Therapeutics Inc., 9390 Towne Centre Drive, San Diego, California 92121, USA. bookser@mbasis.com
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pubmed:publicationType |
Journal Article
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