Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin

We report the discovery of a new potent allosteric effector of sickle cell hemoglobin, GBT440 (<b>36</b>), that increases the affinity of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. Unlike earlier allosteric activators that bind covalently to hemoglobin in a 2:1 stoichiometry, <b>36</b> binds with a 1:1 stoichiometry. Compound <b>36</b> is orally bioavailable and partitions highly and favorably into the red blood cell with a RBC/plasma ratio of ∼150. This partitioning onto the target protein is anticipated to allow therapeutic concentrations to be achieved in the red blood cell at low plasma concentrations. GBT440 (<b>36</b>) is in Phase 3 clinical trials for the treatment of sickle cell disease (NCT03036813).