Discovery of Isohexide Bisglycolamides as Inhibitors of the Integrated Stress Response

ISRIB reactivates protein synthesis for cells under stress through the stabilization of eukaryotic initiation factor 2 beta (eIF2B). We discovered that diaminoisohexides, derived from isomannide and isosorbide serve as a bioisostere for the diamino cyclohexane core in ISRIB. These scaffolds conferred improved solubility but also showed activity for the human ether-a-go-go-related gene (hERG). Herein we describe our efforts to mitigate hERG activity while maintaining target potency. The first high resolution (2.25Å) X-ray cocrystal structure of the eIF2B (α,β,δ)₂ complex with compound <b>7a</b> is reported, which can inform subsequent SAR.