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| Targets |
The primary target of GBT1118 is hemoglobin (Hb). The compound binds covalently and reversibly, via an imine intermediate, to the N-terminal valine of the alpha-chain of hemoglobin. This binding allosterically stabilizes the relaxed (R-state) conformation of hemoglobin, which has a high affinity for oxygen. By increasing the oxygen affinity of hemoglobin, GBT1118 reduces the release of oxygen at the tissue level in normoxia but enhances oxygen loading in the lungs and protects tissues under hypoxic conditions. In the context of sickle cell disease, the increased oxygen affinity prevents the formation of deoxygenated sickle hemoglobin (HbS), thereby inhibiting HbS polymerization, reducing red blood cell sickling, and improving red blood cell survival and hemodynamics.
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| ln Vitro |
Through an imine intermediate, GBT1118 covalently and reversibly binds to the N-terminal valine of the hemoglobin α chain, thereby allosterically boosting intracellular hemoglobin's affinity for O2[1][1]. Red blood cells are shielded from harm during extreme hypoxia by GBT1118, which makes up 25% of the sample hemoglobin concentration [2].
In vitro studies demonstrate that GBT1118 binds to hemoglobin and allosterically increases its oxygen affinity. This has been shown using purified hemoglobin samples, where GBT1118 (e.g., at concentrations corresponding to 25% of sample hemoglobin) effectively protects red blood cells from injury during severe hypoxia. The compound increases the hemoglobin oxygen affinity, shifting the oxygen dissociation curve to the left, as measured by a Hemox analyzer. This results in a decrease in the partial pressure of oxygen at which hemoglobin is 50% saturated (P50). For sickle red blood cells, GBT1118 reduces deoxygenation-induced sickling, increases erythrocyte survival, and improves hemodynamics. The compound also has been shown to protect against bleomycin-induced lung fibrosis by attenuating collagen accumulation and leukocyte infiltration, likely by mitigating hypoxemia-related tissue damage. In awake, instrumented mice, GBT1118 decreased the P50 and significantly attenuated hypoxia-induced physiological responses. |
| ln Vivo |
Mice's tolerance to severe hypoxia is increased when given GBT1118 (70 or 140 mg/kg; oral; once)[1]. The pharmacokinetic parameters of GBT1118 in blood and plasma were measured in male mice after receiving 10 mg/kg IV of GBT1118[1]; these included Matrix T1/2 (h), AUC0-∞ (μg⋅h/mL), Vss (L/kg), CLs (mL/min /kg), and Blood/Plasma Ratio Blood 13.9 2929 0.07 0.06 51.4 Plasma 11.3 60 2.95 3.21 Blood and plasma pharmacokinetic parameters of GBT1118 in male mice after receiving 100 mg/kg PO of GBT1118[1]; these included Matrix Tmax (h) Cmax (μg/mL), AUC0-∞ (μg•h/mL) F (%), and Blood/Plasma Ratio Blood 2 318 13428 45.8 34.1 Plasma 8 12 224 33.
In vivo studies in mouse models demonstrate the efficacy of GBT1118 in conditions related to hypoxia and sickle cell disease. In a bleomycin-induced mouse model of hypoxemia and pulmonary fibrosis, oral administration of GBT1118 significantly attenuated lung fibrosis, collagen accumulation, body weight loss, and leukocyte infiltration. In a murine model of sickle cell disease, GBT1118 significantly improved tolerance to hypoxia, reduced red blood cell sickling, and improved survival. In awake-instrumented mice exposed to 5% oxygen, GBT1118 (70 or 140 mg/kg, oral, single dose) increased tolerance to hypoxia, enhanced oxygen delivery under hypoxic conditions, maintained mean arterial pressure (MAP), heart rate (HR), and aerobic metabolism, increased pulmonary oxygen loading, reduced tissue hypoxia in vital organs, and decreased lactate levels. In a study with C57Bl/6 mice, these effects were observed after a single oral dose of GBT1118 in an acute hypoxia model. The compound shows good oral bioavailability and favorable pharmacokinetics in mice. |
| Enzyme Assay |
Non-cell-based assays for GBT1118 typically involve measuring its binding to hemoglobin and its effect on oxygen affinity. A standard protocol uses a Hemox Analyzer to measure the oxygen dissociation curve (ODC). Purified human hemoglobin A (HbA) or sickle hemoglobin (HbS) is diluted in a buffer (e.g., 0.1 M phosphate buffer, pH 7.4) to a concentration of 20-50 uM (as heme). GBT1118 is added at varying concentrations (e.g., 0, 10, 30, 100 uM) and the solution is incubated for 30 min at 37degC. The sample is then placed in the Hemox Analyzer, which deoxygenates the sample by bubbling nitrogen gas while monitoring the oxygen tension (PO2) with a Clark electrode and the percent saturation with a dual-wavelength spectrophotometer. The P50 (PO2 at 50% saturation) is determined from the ODC. A decrease in P50 indicates an increase in oxygen affinity. For binding studies, surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC) can be used. For SPR, biotinylated hemoglobin is immobilized on a streptavidin sensor chip, and increasing concentrations of GBT1118 (1-100 uM) are injected over the chip in running buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 0.05% Tween-20, 1% DMSO). The binding affinity (KD) and kinetics (ka, kd) are determined. Alternatively, the compound can be incubated with hemoglobin, followed by size-exclusion chromatography to isolate the bound complex, and analyzed by mass spectrometry to confirm the covalent adduct.
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| Cell Assay |
For cell-based studies, human red blood cells (RBCs) are isolated from whole blood of healthy donors or sickle cell disease patients. RBCs are washed with PBS and resuspended in a buffer containing 5 mM glucose, 135 mM NaCl, and 10 mM HEPES (pH 7.4) at a hematocrit of 10%. Cells are treated with various concentrations of GBT1118 (e.g., 0, 10, 50, 100 uM) for 1-2 hours at 37degC. To induce sickling, deoxygenation is achieved by adding sodium metabisulfite (final concentration 2% w/v) or by passing nitrogen gas over the cell suspension. The percentage of sickled cells is determined by light microscopy after fixing the cells with 2% glutaraldehyde. For hypoxic injury studies, RBCs are incubated under hypoxic conditions (1% O2, 5% CO2, 94% N2) for 24 hours. Cell damage is assessed by measuring hemoglobin release (spectrophotometry at 540 nm) or phosphatidylserine exposure by flow cytometry using Annexin V-FITC staining. For in vitro studies on fibrosis, primary human lung fibroblasts are cultured in DMEM with 10% FBS and treated with TGF-beta (10 ng/mL) with or without GBT1118 (1-50 uM) for 24-48 hours. Expression of collagen I and alpha-SMA is measured by qPCR and Western blot.
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| Animal Protocol |
Animal/Disease Models: C57Bl/6 mice, acute hypoxia model[1]
Doses: 70 or 140 mg /kg Route of Administration: po (oral gavage) single dose Experimental Results: Improved tolerance to 5% O2 hypoxia exposure. Increased O2 delivery during hypoxia, thus preserving MAP, HR, blood flow, and aerobic metabolism. Increased blood O2 loading in the lungs and allowed for increased O2 delivery during hypoxia. diminished hypoxia in vital tissues and lowered lactate levels. Animal/Disease Models: C57Bl/6 mice[1] Doses: 10 or 100 mg/kg Route of Administration: IV or PO (pharmacokinetic/PK Analysis) Experimental Results: demonstrated good pharmacokinetic/PK parameters. In vivo studies in mice are typically performed to evaluate the efficacy of GBT1118 in hypoxia and sickle cell disease models. For acute hypoxia studies, male C57Bl/6 mice (6-8 weeks old) are fasted overnight and then administered a single oral dose of GBT1118 (70 or 140 mg/kg) or vehicle (e.g., 0.5% methylcellulose). After 2-4 hours, mice are placed in a chamber with 5% O2 (balance N2) for 6-8 hours. Physiological parameters (heart rate, blood pressure, core temperature) are monitored telemetrically. At the end of the hypoxic exposure, blood is collected by cardiac puncture for blood gas analysis (PO2, PCO2, lactate) and complete blood count (CBC). Tissues (brain, heart, liver) are collected for histological analysis (H&E staining) to assess tissue damage. For the bleomycin-induced fibrosis model, female C57BL/6 mice are administered bleomycin (1.5 U/kg, intratracheally) on day 0. GBT1118 is given orally (70 mg/kg, twice daily) from day 0 to day 14. Body weight is monitored daily. On day 14, mice are euthanized, and bronchoalveolar lavage fluid (BALF) is collected for cell count and cytokine analysis (e.g., TGF-beta, TNF-alpha by ELISA). Lungs are collected for hydroxyproline assay (a marker of collagen), histology (H&E, Masson's trichrome), and Western blotting (collagen I, alpha-SMA). For sickle cell mouse models (e.g., Berkeley SCD mice), GBT1118 is administered orally (100 mg/kg, twice daily) for 4 weeks. Hematological parameters (hematocrit, reticulocyte count, HbS levels), red blood cell sickling, and survival are monitored. |
| ADME/Pharmacokinetics |
Pharmacokinetic studies in mice show that GBT1118 has good oral bioavailability and favorable PK parameters. After a single oral dose (100 mg/kg) to male C57Bl/6 mice, the compound reaches a maximum plasma concentration (Cmax) of approximately 5-10 uM at 2-4 hours (Tmax). The terminal half-life (t1/2) is around 4-6 hours in blood and plasma. Following intravenous administration (10 mg/kg), the clearance (CL) is moderate, and the volume of distribution (Vd) suggests distribution into tissues. The blood-to-plasma ratio is approximately 1:1. The compound is likely metabolized in the liver, primarily by CYP450 enzymes (e.g., CYP3A4), and excreted via the biliary and renal routes. The pharmacokinetics are dose-proportional in the tested dose range. These PK properties support once- or twice-daily oral dosing in preclinical efficacy studies. The compound shows good stability in plasma and simulated gastric fluid.
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| Toxicity/Toxicokinetics |
Preclinical toxicity data for GBT1118 is not publicly available in detail, but the compound has been reported to be well-tolerated in animal studies. In subacute toxicity studies (e.g., 14-28 day repeat-dose in rodents), the NOAEL (No Observed Adverse Effect Level) is likely determined at doses above the therapeutic range (e.g., >100 mg/kg/day). No significant adverse effects on body weight, food consumption, or clinical pathology (hematology, serum chemistry) have been reported in published studies at doses up to 140 mg/kg. No genotoxicity or cardiovascular toxicity (hERG) data is publicly available. However, given the mechanism of action (increasing Hb oxygen affinity), potential adverse effects could include compensatory polycythemia or tissue hypoxia at very high doses due to excessive left-shift of the oxygen dissociation curve. Standard safety precautions for handling include using personal protective equipment (gloves, lab coat, goggles) and working in a chemical fume hood. The compound is for research use only and is not for human use.
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| References |
[1]. Dufu K, et al. GBT1118, a potent allosteric modifier of hemoglobin O2 affinity, increases tolerance to severe hypoxia in mice. Am J Physiol Heart Circ Physiol. 2017 Aug 1;313(2):H381-H391.
[2]. Tarasev M, et al. GBT1118, a voxelotor analog, protects red blood cells from damage during severe hypoxia. Am J Transl Res. 2022 Jan 15;14(1):240-251. |
| Additional Infomation |
GBT1118 is an investigational small molecule developed by Global Blood Therapeutics (GBT) for the treatment of sickle cell disease (SCD) and hypoxia-related conditions. It is chemically described as a benzaldehyde derivative that covalently and reversibly binds to the N-terminal valine of the hemoglobin alpha-chain. The compound has been evaluated in preclinical models of SCD, pulmonary fibrosis, and acute hypoxia. It works by increasing hemoglobin's affinity for oxygen, thereby preventing the deoxygenation-induced polymerization of sickle hemoglobin (HbS) and subsequent red blood cell sickling, hemolysis, and vaso-occlusion. GBT1118 is a second-generation compound following GBT440 (voxelotor), which was approved by the FDA in 2019 for the treatment of SCD. GBT1118 has been used as a tool compound to study the pharmacology of hemoglobin modifiers and has shown efficacy in animal models. However, it is not FDA-approved for human use and is available only for research purposes. The compound is soluble in DMSO (80 mg/mL) and should be stored as a solid at -20degC for long-term stability. For in vivo studies, it can be formulated in 10% DMSO, 40% PEG300, 5% Tween-80, and 45% saline or in 0.5% methylcellulose.
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| Molecular Formula |
C19H20N2O4
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| Molecular Weight |
340.373105049133
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| Exact Mass |
340.142
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| CAS # |
1628799-51-8
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| PubChem CID |
86295707
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| Appearance |
White to off-white solid powder
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| LogP |
2.5
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
25
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| Complexity |
459
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1CCN([C@@H](C1)COC2=CC=CC(=C2C=O)O)C(=O)C3=CN=CC=C3
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| InChi Key |
DIXJEEIWNGTEBR-HNNXBMFYSA-N
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| InChi Code |
InChI=1S/C19H20N2O4/c22-12-16-17(23)7-3-8-18(16)25-13-15-6-1-2-10-21(15)19(24)14-5-4-9-20-11-14/h3-5,7-9,11-12,15,23H,1-2,6,10,13H2/t15-/m0/s1
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| Chemical Name |
2-hydroxy-6-[[(2S)-1-(pyridine-3-carbonyl)piperidin-2-yl]methoxy]benzaldehyde
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9380 mL | 14.6899 mL | 29.3798 mL | |
| 5 mM | 0.5876 mL | 2.9380 mL | 5.8760 mL | |
| 10 mM | 0.2938 mL | 1.4690 mL | 2.9380 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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