Structure-based optimization of novel azepane derivatives as PKB inhibitors

A finales del siglo XIX, Medellín aún conservaba rasgos que la conectaban con su pasado colonial de pequeña villa. La vida monótona sin más diversiones que ir a la iglesia a la misa matinal y la Fiesta de la Virgen de La Candelaria, que había perdido la escasa pero no nula espectacularidad del siglo XVIII, eran, a decir de los periódicos locales, los únicos ratos de solaz que tenían lugar allí. No obstante, durante esa última década, Medellín degustó la ópera y la zarzuela que trajeron tres compañías extranjeras, a las tablas del único escenario con el que contaba en ese entonces. Y esas compañías entregaron lo mejor de sus caracterizaciones y un poco más de su música, e hicieron vibrar a los concurrentes al Teatro Principal con lo más escogido del repertorio italiano, español y francés. Así mismo, dichas compañías se unieron a causas nobles, entregando el producido de algunas de sus funciones para apoyar la labor de instituciones de caridad locales

Structure-based optimization of novel azepane derivatives as PKB Inhibitors

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