GFB-8438 is a novel, highly potent and subtype specific TRPC5 inhibitor with IC50s of 0.18 and 0.29 μM of hTRPC5 and hTRPC4, respectively. It shows excellent selectivity against TRPC6, other TRP family members, NaV 1.5, as well as limited activity against the hERG channel. GFB-8438 protects mouse podocytes from injury induced by protamine sulfate model.
Physicochemical Properties
| Molecular Formula | C₁₆H₁₄CLF₃N₄O₂ |
| Molecular Weight | 386.7562 |
| Exact Mass | 386.075 |
| CAS # | 2304549-73-1 |
| PubChem CID | 138471783 |
| Appearance | Off-white to light yellow solid powder |
| Density | 1.52±0.1 g/cm3(Predicted) |
| LogP | 2.1 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 3 |
| Heavy Atom Count | 26 |
| Complexity | 650 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | MITRKIWBJVJRAM-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C16H14ClF3N4O2/c17-14-12(7-21-22-15(14)26)23-5-6-24(13(25)9-23)8-10-3-1-2-4-11(10)16(18,19)20/h1-4,7H,5-6,8-9H2,(H,22,26) |
| Chemical Name | 4-chloro-5-(3-oxo-4-(2-(trifluoromethyl)benzyl)piperazin-1-yl)pyridazin-3(2H)-one |
| Synonyms | GFB-8438 GFB 8438 GFB8438 |
| 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 | GFB-8438 (1 μM) pretreatment of mouse podocytes for 30 min, followed by protamine sulfate incubation, substantially prevented synaptopodin loss and cytoskeletal remodeling[1]. |
| ln Vivo | In a hypertensive deoxycorticosterone acetate (DOCA)-salt rat model of focal segmental glomerulosclerosis (FSGS), GFB-8438 (30 mg/kg; sc; daily for 3 weeks) is effective in lowering both total protein and albumin concentrations in urine[1]. Cl, VSS, and t1/2 were 31 mL/min/kg, 1.17 L/kg, and 0.5 hours, respectively, following GFB-8438 (1 mg/kg; IV) treatment[1]. |
| Animal Protocol |
Animal/Disease Models: Sprague Dawley rats (DOCA-salt rat model of FSGS)[1] Doses: 30 mg/kg Route of Administration: sc; daily for 3 weeks Experimental Results: Significant reduction in urine protein concentrations. Animal/Disease Models: 6-8 weeks old male SD rats[1] Doses: 1 mg/kg Route of Administration: iv (pharmacokinetic/PK Analysis) Experimental Results: The Cl, Vss, and t1/2 were 31 mL/min/kg, 1.17 L/kg, and 0.5 hrs (hours), respectively. |
| References |
[1]. Discovery of a Potent and Selective TRPC5 Inhibitor, Efficacious in a Focal Segmental Glomerulosclerosis Model.ACS Med Chem Lett. 2019 Oct 22;10(11):1579-1585. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~83.33 mg/mL (~215.46 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.38 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 20.8 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: ≥ 2.08 mg/mL (5.38 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (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 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.08 mg/mL (5.38 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 20.8 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 | 2.5856 mL | 12.9279 mL | 25.8558 mL | |
| 5 mM | 0.5171 mL | 2.5856 mL | 5.1712 mL | |
| 10 mM | 0.2586 mL | 1.2928 mL | 2.5856 mL |