GBT1118 is a potent, orally active compound that serves as an allosteric modulator of hemoglobin oxygen affinity, enhancing tolerance to severe hypoxia [1].

GBT1118 forms a covalent and reversible bond with the N-terminal valine of the alpha chain of hemoglobin through an imine intermediate, allosterically enhancing the affinity of intracellular hemoglobin for O2 [1]. At concentrations equivalent to 25% of sample hemoglobin, GBT1118 can protect red blood cells from damage during severe hypoxia [2].

GBT1118, at dosages of 70 or 140 mg/kg administered orally once, enhanced the tolerance of mice to severe hypoxemia [1]. In pharmacokinetic analyses, male mice receiving 10 mg/kg intravenously showed a blood half-life of 13.9 hours and plasma half-life of 11.3 hours, with blood and plasma area under the curve (AUC) at 2929 μg⋅h/mL and 60 μg⋅h/mL respectively. The steady state volume of distribution (Vss) and systemic clearance (CLs) in blood were 0.07 L/kg and 0.06 mL/min/kg, with a blood/plasma ratio of 51.4. Following 100 mg/kg orally, the time to reach maximum concentration (Tmax) in blood was 2 hours with a peak concentration (Cmax) of 318 μg/mL, while in plasma, Tmax was 8 hours with a Cmax of 12 μg/mL. The AUC was 13428 μg•h/mL in blood and 224 μg•h/mL in plasma, and bioavailability (F%) was found to be 45.8% and 33.5% respectively. In an acute hypoxia model with C57Bl/6 mice, a single oral dose improved their tolerance to a 5% O2 environment, facilitated greater oxygen delivery during hypoxic conditions maintaining mean arterial pressure (MAP), heart rate (HR), blood flow, and aerobic metabolism, and increased oxygen saturation in lung blood. This also led to reduced hypoxemia in vital tissues and decreased lactate levels [1].