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FG-2216 (YM311; IOX3; YM311) is a novel, potent, and orally bioactive inhibitor of hypoxia-inducible factor-1α (HIF) prolyl 4-hydroxylase (PHD) with the potential to treat anemia. It inhibits HIF-PHD with an IC50 of 3.9 μM.
Physicochemical Properties
| Molecular Formula | C12H9CLN2O4 |
| Molecular Weight | 280.6639 |
| Exact Mass | 280.025 |
| Elemental Analysis | C, 51.35; H, 3.23; Cl, 12.63; N, 9.98; O, 22.80 |
| CAS # | 223387-75-5 |
| Related CAS # | 223387-75-5 |
| PubChem CID | 6914666 |
| Appearance | White to off-white solid powder |
| LogP | 1.799 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 3 |
| Heavy Atom Count | 19 |
| Complexity | 366 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | ClC1C2=C([H])C([H])=C([H])C([H])=C2C(=C(C(N([H])C([H])([H])C(=O)O[H])=O)N=1)O[H] |
| InChi Key | OUQVKRKGTAUJQA-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C12H9ClN2O4/c13-11-7-4-2-1-3-6(7)10(18)9(15-11)12(19)14-5-8(16)17/h1-4,18H,5H2,(H,14,19)(H,16,17) |
| Chemical Name | 2-[(1-chloro-4-hydroxyisoquinoline-3-carbonyl)amino]acetic acid |
| Synonyms | IOX3;IOX 3;IOX-3;FG-2216; FG 2216; FG2216; YM311; YM-311; YM 311. |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| ln Vitro | In Hep3B cells, FG-2216 (50-100 μM; 24 h) increases erythropoietin (Epo) secretion through PHD2 inhibition[1]. In Hep3B cells, FG-2216 (3-100 μM; 24 h) stabilizes HIF-1α and HIF-2α[1]. |
| ln Vivo | Rhesus macaques respond well to FG-2216 (40–60 mg/kg; po twice weekly for 150 days), which causes erythropoiesis and a little increase in hemoglobin (HbF) expression[2]. In mice, FG-2216 (50 mg/ kg; po once daily for 4 or 12 d) raises hemoglobin levels, red blood cell counts, and hematocrit[1]. In rhesus macaques, FG-2216 (40–60 mg/kg; one po) reversibly produces endogenous Epo [2]. |
| Animal Protocol |
Animal/Disease Models: Male rhesus macaques (3-6 years; 4-7 kg) mice are treated with large-volume phlebotomy with iron supplementation[2] Doses: 40, 60 mg/kg Route of Administration: Po (40 mg/ kg) twice a week for 6-8 weeks Po (60 mg/kg) twice a week for 6-8 weeks Po (60 mg/kg) twice a week for 6-8 weeks Experimental Results: demonstrated reticulocytosis within 1-2 weeks of dosing. Increased total hemoglobin levels at the end of the study duration. |
| References |
[1]. [(4-Hydroxyl-benzo[4,5]thieno[3,2-c]pyridine-3-carbonyl)-amino]-acetic acid derivatives; HIF prolyl 4-hydroxylase inhibitors as oral erythropoietin secretagogues. Bioorg Med Chem Lett. 2013 Nov 1;23(21):5953-7. [2]. HIF prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques. Blood. 2007 Sep 15;110(6):2140-7. [3]. Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. J Am Soc Nephrol. 2010 Dec;21(12):2151-6. |
| Additional Infomation |
A orally active prolyl-hydroxylase inhibitor which can stabilize hypoxia-inducible transcription factor independent of oxygen availability. Drug Indication Investigated for use/treatment in anemia and kidney disease. |
Solubility Data
| Solubility (In Vitro) | DMSO: 56 mg/mL (199.5 mM) Water:<1 mg/mL Ethanol:<1 mg/mL |
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (8.91 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (8.91 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.5630 mL | 17.8152 mL | 35.6303 mL | |
| 5 mM | 0.7126 mL | 3.5630 mL | 7.1261 mL | |
| 10 mM | 0.3563 mL | 1.7815 mL | 3.5630 mL |