Potent Antisickling Furaldehyde Analogs for Acute Sickle Cell Therapy: Enhanced Efficacy and Intravenous Formulation Potential.

Abstract

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.