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Crystal Structure of Protein Kinase A in Complex with Azepane Derivative 4

OverviewOverview

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]-azepa, n-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.

About this StructureAbout this Structure

1SVG is a Protein complex structure of sequences from Bos taurus with I04 as ligand. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.

ReferenceReference

Structure-based optimization of novel azepane derivatives as PKB inhibitors., Breitenlechner CB, Wegge T, Berillon L, Graul K, Marzenell K, Friebe WG, Thomas U, Schumacher R, Huber R, Engh RA, Masjost B, J Med Chem. 2004 Mar 11;47(6):1375-90. PMID:14998327

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