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PDBsum entry 1sve
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References listed in PDB file
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Key reference
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Title
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Structure-Based optimization of novel azepane derivatives as pkb inhibitors.
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Authors
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C.B.Breitenlechner,
T.Wegge,
L.Berillon,
K.Graul,
K.Marzenell,
W.G.Friebe,
U.Thomas,
R.Schumacher,
R.Huber,
R.A.Engh,
B.Masjost.
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Ref.
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J Med Chem, 2004,
47,
1375-1390.
[DOI no: ]
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PubMed id
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Abstract
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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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