Abstact

The integrated stress response (ISR) is a highly conserved cellular pathway triggered by a variety of insults, reducing protein synthesis and inducing ATF4, leading to broadly remodeling the cellular transcriptome and metabolome. ISRIB, 1, the first identified eIF2B activator, attenuates the ISR restoring protein synthesis, but its poor solubility limits absorption and advancement. To improve drug-like properties, we explored replacements for both the cyclohexyl core and side chains of ISRIB. This effort initially led to truncated analogue, 2BAct, 13, which demonstrated improved solubility relative to 1; however, cardiovascular effects in higher species limited its progression into the clinic. Potent analogue 9 was identified with significantly improved solubility vs 1 but was still projected to have solubility-limited absorption. A prodrug campaign resulted in the identification of compound 26 (fosigotifator), which exhibited significantly improved solubility and is currently being investigated in the clinic.