| http://purl.uniprot.org/citations/14998327 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/14998327 | http://www.w3.org/2000/01/rdf-schema#comment | "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."xsd:string |
| http://purl.uniprot.org/citations/14998327 | http://purl.org/dc/terms/identifier | "doi:10.1021/jm0310479"xsd:string |
| http://purl.uniprot.org/citations/14998327 | http://purl.uniprot.org/core/author | "Huber R."xsd:string |
| http://purl.uniprot.org/citations/14998327 | http://purl.uniprot.org/core/author | "Engh R.A."xsd:string |
| http://purl.uniprot.org/citations/14998327 | http://purl.uniprot.org/core/author | "Thomas U."xsd:string |
| http://purl.uniprot.org/citations/14998327 | http://purl.uniprot.org/core/author | "Masjost B."xsd:string |
| http://purl.uniprot.org/citations/14998327 | http://purl.uniprot.org/core/author | "Schumacher R."xsd:string |
| http://purl.uniprot.org/citations/14998327 | http://purl.uniprot.org/core/author | "Breitenlechner C.B."xsd:string |
| http://purl.uniprot.org/citations/14998327 | http://purl.uniprot.org/core/author | "Berillon L."xsd:string |
| http://purl.uniprot.org/citations/14998327 | http://purl.uniprot.org/core/author | "Friebe W.G."xsd:string |
| http://purl.uniprot.org/citations/14998327 | http://purl.uniprot.org/core/author | "Graul K."xsd:string |
| http://purl.uniprot.org/citations/14998327 | http://purl.uniprot.org/core/author | "Marzenell K."xsd:string |
| http://purl.uniprot.org/citations/14998327 | http://purl.uniprot.org/core/author | "Wegge T."xsd:string |
| http://purl.uniprot.org/citations/14998327 | http://purl.uniprot.org/core/date | "2004"xsd:gYear |
| http://purl.uniprot.org/citations/14998327 | http://purl.uniprot.org/core/name | "J Med Chem"xsd:string |
| http://purl.uniprot.org/citations/14998327 | http://purl.uniprot.org/core/pages | "1375-1390"xsd:string |
| http://purl.uniprot.org/citations/14998327 | http://purl.uniprot.org/core/title | "Structure-based optimization of novel azepane derivatives as PKB inhibitors."xsd:string |
| http://purl.uniprot.org/citations/14998327 | http://purl.uniprot.org/core/volume | "47"xsd:string |
| http://purl.uniprot.org/citations/14998327 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/14998327 |
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