Source:http://linkedlifedata.com/resource/pubmed/id/14998327
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
6
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| pubmed:dateCreated |
2004-3-4
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| pubmed:abstractText |
Novel azepane derivatives were prepared and evaluated for protein kinase B (PKB-alpha) and protein kinase A (PKA) inhibition. The original (-)-balanol-derived lead structure (4R)-4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoic acid (3R)-3-[(pyridine-4-carbonyl)amino]-azepan-4-yl ester (1) (IC(50) (PKB-alpha) = 5 nM) which contains an ester moiety was found to be plasma unstable and therefore unsuitable as a drug. Based upon molecular modeling studies using the crystal structure of the complex between PKA and 1, the five compounds N-[(3R,4R)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoylamino]-azepan-3-yl]-isonicotinamide (4), (3R,4R)-N-[4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzyloxy]-azepan-3-yl]-isonicotinamide (5), N-[(3R,4S)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-phenylamino]-methyl]-azepan-3-yl)-isonicotinamide (6), N-[(3R,4R)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzylamino]-azepan-3-yl]-isonicotinamide (7), and N-[(3R,4S)-4-(4-[trans-2-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-phenyl]-vinyl]-azepan-3-yl)-isonicotinamide (8) with linkers isosteric to the ester were designed, synthesized, and tested for in vitro inhibitory activity against PKA and PKB-alpha and for plasma stability in mouse plasma.(1) Compound 4 was found to be plasma stable and highly active (IC(50) (PKB-alpha) = 4 nM). Cocrystals with PKA were obtained for 4, 5, and 8 and analyzed for binding interactions and conformational changes in the ligands and protein in order to rationalize the different activities of the molecules.
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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/Azepines,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-akt
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| pubmed:status |
MEDLINE
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| pubmed:month |
Mar
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| pubmed:issn |
0022-2623
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| pubmed:author |
pubmed-author:BerillonLaurentL,
pubmed-author:BreitenlechnerChristine BCB,
pubmed-author:EnghRichard ARA,
pubmed-author:FriebeWalter-GunarWG,
pubmed-author:GraulKlausK,
pubmed-author:HuberRobertR,
pubmed-author:MarzenellKlausK,
pubmed-author:MasjostBirgitB,
pubmed-author:SchumacherRalfR,
pubmed-author:ThomasUlrikeU,
pubmed-author:WeggeThomasT
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| pubmed:issnType |
Print
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| pubmed:day |
11
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| pubmed:volume |
47
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
1375-90
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| pubmed:dateRevised |
2009-11-19
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| pubmed:meshHeading |
pubmed-meshheading:14998327-Animals,
pubmed-meshheading:14998327-Azepines,
pubmed-meshheading:14998327-Binding Sites,
pubmed-meshheading:14998327-Crystallography, X-Ray,
pubmed-meshheading:14998327-Drug Stability,
pubmed-meshheading:14998327-Mice,
pubmed-meshheading:14998327-Models, Molecular,
pubmed-meshheading:14998327-Molecular Structure,
pubmed-meshheading:14998327-Protein Binding,
pubmed-meshheading:14998327-Protein-Serine-Threonine Kinases,
pubmed-meshheading:14998327-Proto-Oncogene Proteins,
pubmed-meshheading:14998327-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:14998327-Structure-Activity Relationship
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| pubmed:year |
2004
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| pubmed:articleTitle |
Structure-based optimization of novel azepane derivatives as PKB inhibitors.
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| pubmed:affiliation |
Pharma Research, Roche Diagnostics GmbH, Werk Penzberg, Nonnenwald 2, D-82372 Penzberg, Germany. birgit.masjost@roche.com
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| pubmed:publicationType |
Journal Article
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