Design and synthesis of pyridine–pyrazolopyridine-based inhibitors of protein kinase B/Akt

Thr-211 is one of three different amino acid residues in the kinase domain of protein kinase B/Akt as compared to protein kinase A (PKA), a closely related analog in the same AGC family. In an attempt to improve the potency and selectivity of our indazole–pyridine series of Akt inhibitors over PKA, efforts have focused on the incorporation of a chemical functionality to interact with the hydroxy group of Thr-211. Several substituents including an oxygen anion, amino, and nitro groups have been introduced at the C-6 position of the indazole scaffold, leading to a significant drop in Akt potency. Incorporation of a nitrogen atom into the phenyl ring at the same position (i.e., 9f) maintained the Akt activity and, in some cases, improved the selectivity over PKA. The structure–activity relationships of the new pyridine–pyrazolopyridine series of Akt inhibitors and their structural features when bound to PKA are also discussed.

We have designed and synthesized a series of potent pyridine–pyrazolopyridine-based inhibitors of protein kinase B/Akt. The best compound in this series showed 0.6 nM IC50 against Akt and 180-fold selectivity over protein kinase A (PKA). The structure–activity relationships of these compounds and their structural features when bound to PKA are also discussed.Figure optionsDownload as PowerPoint slide