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ACS Med Chem Lett. 2017 Jan 23;8(3):321-326. doi: 10.1021/acsmedchemlett.6b00491. eCollection 2017 Mar 9.

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

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Global Blood Therapeutics, Inc. , South San Francisco, California 94080, United States.
Cytokinetics, Inc. , South San Francisco, California 94080, United States.
Albert Einstein College of Medicine , Bronx, New York 10461, United States.
Department of Pharmaceutical Chemistry, University of California , San Francisco, California 94158, United States.
Tandem Sciences, Inc. , Menlo Park, California 94025, United States.


We report the discovery of a new potent allosteric effector of sickle cell hemoglobin, GBT440 (36), 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, 36 binds with a 1:1 stoichiometry. Compound 36 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 (36) is in Phase 3 clinical trials for the treatment of sickle cell disease (NCT03036813).


Schiff-base formation; Sickle cell disease; aldehyde; allosteric modulator; oxygen affinity; red blood cell partitioning; sickle cell hemoglobin

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