Source:http://linkedlifedata.com/resource/pubmed/id/17523610
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
13
|
| pubmed:dateCreated |
2007-6-21
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| pubmed:abstractText |
Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
Jun
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| pubmed:issn |
0022-2623
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| pubmed:author |
pubmed-author:BouskaJenniferJ,
pubmed-author:CampbellThomas JTJ,
pubmed-author:DieboldR BruceRB,
pubmed-author:GandhiViraj BVB,
pubmed-author:GintantGary AGA,
pubmed-author:GirandaVincent LVL,
pubmed-author:GongJianchunJ,
pubmed-author:GuanRanR,
pubmed-author:JohnsonEric FEF,
pubmed-author:KlinghoferVeredV,
pubmed-author:LiQunQ,
pubmed-author:LiTongmeiT,
pubmed-author:LiuXuesongX,
pubmed-author:LuoYanY,
pubmed-author:MamoMulugetaM,
pubmed-author:MarshKennan CKC,
pubmed-author:MartinRuth LRL,
pubmed-author:OlsonAmandaA,
pubmed-author:PenningThomas DTD,
pubmed-author:PolakowskiJamesJ,
pubmed-author:RosenbergSaul HSH,
pubmed-author:SongXiaohongX,
pubmed-author:StollVincent SVS,
pubmed-author:ThomasSheelaS,
pubmed-author:WoodsKeith WKW,
pubmed-author:ZhuGui-DongGD
|
| pubmed:issnType |
Print
|
| pubmed:day |
28
|
| pubmed:volume |
50
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
2990-3003
|
| pubmed:dateRevised |
2009-11-19
|
| pubmed:meshHeading |
pubmed-meshheading:17523610-Administration, Oral,
pubmed-meshheading:17523610-Animals,
pubmed-meshheading:17523610-Biological Availability,
pubmed-meshheading:17523610-Crystallography, X-Ray,
pubmed-meshheading:17523610-Dogs,
pubmed-meshheading:17523610-Hypotension,
pubmed-meshheading:17523610-Indazoles,
pubmed-meshheading:17523610-Mice,
pubmed-meshheading:17523610-Models, Molecular,
pubmed-meshheading:17523610-Protein Conformation,
pubmed-meshheading:17523610-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:17523610-Purkinje Fibers,
pubmed-meshheading:17523610-Pyrazoles,
pubmed-meshheading:17523610-Pyridines,
pubmed-meshheading:17523610-Rats,
pubmed-meshheading:17523610-Stereoisomerism,
pubmed-meshheading:17523610-Structure-Activity Relationship
|
| pubmed:year |
2007
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| pubmed:articleTitle |
Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase B/Akt inhibitors with reduced hypotension.
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| pubmed:affiliation |
Cancer Research, Preclinical Safety, Structural Biology, Integrative Pharmacology, GPRD, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6101, USA. gui-dong.zhu@abbott.com
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| pubmed:publicationType |
Journal Article
|