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Structure-based optimization of novel azepane derivatives as PKB Inhibitors

Breitenlechner, Christine B., Wegge, Thomas, Berillon, Laurent, Graul, Klaus, Marzenell, Klaus, Friebe, Walter-Gunar, Thomas, Ulrike, Schumacher, Ralf, Huber, Robert, Engh, Richard A. and Masjost, Birgit 2004. Structure-based optimization of novel azepane derivatives as PKB Inhibitors. Journal of Medicinal Chemistry 47 (6) , pp. 1375-1390. 10.1021/jm0310479

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Novel azepane derivatives were prepared and evaluated for protein kinase B (PKB-α) 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) (IC50 (PKB-α) = 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-α and for plasma stability in mouse plasma.1 Compound 4 was found to be plasma stable and highly active (IC50 (PKB-α) = 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
ISSN: 0022-2623
Last Modified: 24 Jun 2017 11:00

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