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rdf:type |
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lifeskim:mentions |
umls-concept:C0009226,
umls-concept:C0030016,
umls-concept:C0039808,
umls-concept:C0181090,
umls-concept:C0243077,
umls-concept:C0302614,
umls-concept:C0360714,
umls-concept:C0678594,
umls-concept:C1527178,
umls-concept:C1705938,
umls-concept:C1706050,
umls-concept:C1707689
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pubmed:issue |
13
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pubmed:dateCreated |
2008-7-3
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pubmed:abstractText |
Clinical studies have demonstrated that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) inhibitors, are effective at lowering mortality levels associated with cardiovascular disease; however, 2-7% of patients may experience statin-induced myalgia that limits compliance with a treatment regimen. High resolution crystal structures, thermodynamic binding parameters, and biochemical data were used to design statin inhibitors with improved HMGR affinity and therapeutic index relative to statin-induced myalgia. These studies facilitated the identification of imidazole 1 as a potent (IC 50 = 7.9 nM) inhibitor with excellent hepatoselectivity (>1000-fold) and good in vivo efficacy. The binding of 1 to HMGR was found to be enthalpically driven with a Delta H of -17.7 kcal/M. Additionally, a second novel series of bicyclic pyrrole-based inhibitors was identified that induced order in a protein flap of HMGR. Similar ordering was detected in a substrate complex, but has not been reported in previous statin inhibitor complexes with HMGR.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:BainbridgeGraemeG,
pubmed-author:BillsElizabethE,
pubmed-author:BoltonGaryG,
pubmed-author:BrattonLarry DLD,
pubmed-author:CaspersNicole LNL,
pubmed-author:DunbarJames BJB,
pubmed-author:HarrisMelissa SMS,
pubmed-author:HutchingsRichard HRH,
pubmed-author:KennedyRobert MRM,
pubmed-author:LarsenScott DSD,
pubmed-author:PavlovskyAlexanderA,
pubmed-author:PfefferkornJeffrey AJA,
pubmed-author:SarverRonald WRW
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pubmed:issnType |
Electronic
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pubmed:day |
10
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pubmed:volume |
51
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3804-13
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pubmed:meshHeading |
pubmed-meshheading:18540668-Animals,
pubmed-meshheading:18540668-Binding Sites,
pubmed-meshheading:18540668-Calorimetry,
pubmed-meshheading:18540668-Cells, Cultured,
pubmed-meshheading:18540668-Crystallography, X-Ray,
pubmed-meshheading:18540668-Drug Design,
pubmed-meshheading:18540668-Fluorobenzenes,
pubmed-meshheading:18540668-Hepatocytes,
pubmed-meshheading:18540668-Hydroxymethylglutaryl CoA Reductases,
pubmed-meshheading:18540668-Hydroxymethylglutaryl-CoA Reductase Inhibitors,
pubmed-meshheading:18540668-Imidazoles,
pubmed-meshheading:18540668-Mice,
pubmed-meshheading:18540668-Microsomes, Liver,
pubmed-meshheading:18540668-Models, Molecular,
pubmed-meshheading:18540668-Molecular Structure,
pubmed-meshheading:18540668-Muscle Cells,
pubmed-meshheading:18540668-Pyrimidines,
pubmed-meshheading:18540668-Pyrroles,
pubmed-meshheading:18540668-Rats,
pubmed-meshheading:18540668-Structure-Activity Relationship,
pubmed-meshheading:18540668-Sulfonamides,
pubmed-meshheading:18540668-Thermodynamics
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pubmed:year |
2008
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pubmed:articleTitle |
Thermodynamic and structure guided design of statin based inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase.
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pubmed:affiliation |
Pfizer Global Research & Development, Ann Arbor, Michigan 48105, USA. Ronald.w.sarver@pfizer.com
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pubmed:publicationType |
Journal Article
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