MMA509

Sickle cell disease (SCD) is a debilitating inherited blood disorder characterized by acute crises that require immediate intervention. Aromatic aldehydes that increase hemoglobin (Hb) oxygen affinity (e.g., 5‐HMF) can prevent hypoxia‐induced erythrocyte sickling, but clinical efforts have been hindered by insufficient potency or poor pharmacokinetics. Herein, analogs of 5‐HMF (MMA‐500 series of compounds) are reported to retain 5‐HMF positive physicochemical and pharmacodynamic properties, including safety, solubility, and relatively short duration of action that are essential for their acute use. Two analogs, MMA503 and MMA509, demonstrate over 3.3‐fold greater in vitro antisickling activity than 5‐HMF. This potency is evidenced by significantly enhanced Hb adduct formation, increased oxygen affinity, and robust inhibition of red blood cell sickling in sickle blood assays. X‐ray crystallography further elucidates the Hb binding interactions underlying their potency at the molecular level. MMA509 emerges as a lead candidate and is advanced to formulation studies. An IV formulation of MMA509 in 40% polyethylene glycol 400 achieves ≈13.5 mg mL −1 solubility, enabling rapid attainment of therapeutic drug levels. The potent pharmacologic profile of MMA509, combined with its successful parenteral formulation, highlights its promise as a fast‐acting therapeutic for acute SCD crises as a result of rapid onset expected from IV dosing.