| Size | Price | Stock | Qty |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg |
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| Other Sizes |
| Targets |
TRPC5 (IC50 = 14.7 μM in whole-cell patch-clamp experiments) [1]
No blocking activity against TRPC4 or TRPC6 even at high micromolar concentrations [1] |
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| ln Vitro |
The brain and kidney have high expression levels of TRPC5, a non-selective cation channel that is permeable to Ca2+. Even in patch-clamp electrophysiological investigations, AC1903 (0-100 µM) suppresses riluzole-activated TRPC5 whole-cell currents, but not carbachol (CCh)-induced TRPC4 or OAG-induced TRPC6 currents. At high micromolar quantities, this is also true. ML204 (IC50=13.6 μM) and AC1903 (IC50=14.7 μM) exhibit nearly comparable ICIC50 values in human embryonic kidney 293 (HEK-293) cells that express TRPC5 [1]. When applied to both wild-type podocytes and podocytes expressing a mutant angiotensin II type 1 (AT1) receptor that is not inactivatable, AC1903 (30 µM) reduces the formation of reactive oxygen species (ROS) generated by angiotensin II[1]. AC1903 (30 µM) inhibits the production of ROS by caAT1R. Within 36 hours of caAT1R expression, there was an increase in podocyte death; however, AC1903 prevented podocytes from dying [1].
In HEK-293 cells expressing TRPC5, TRPC4, or TRPC6, AC1903 selectively blocked riluzole-activated TRPC5 whole-cell currents in a dose-dependent manner (IC50 = 14.7 μM), but failed to block carbachol-induced TRPC4 currents or OAG-induced TRPC6 currents even at high micromolar concentrations (1 to 100 μM) [1]. In cultured wild-type podocytes, treatment with AngII (10 μM) induced a significant increase in reactive oxygen species (ROS) production; AC1903 (30 μM) blocked this ROS generation, comparable to the ROS scavenger N-acetylcysteine [1]. In podocytes engineered to overexpress a constitutively active mutant of human AT1R (caAT1R), AC1903 (30 μM) blocked caAT1R-induced ROS generation [1]. In caAT1R-expressing podocytes, AC1903 (30 μM) protected against increased podocyte cell death observed within 36 hours of caAT1R expression [1]. |
| ln Vivo |
In an AT1 receptor transgenic nephropathy rat model, AC1903 (ip; 50 mg/kg; twice daily; 7 days) effectively suppresses proteinuria and decreases pseudocyst development and podocyte loss [1]. When administered intraperitoneally twice daily at a dose of 50 mg/kg, commencing on day 7 and continuing for one week until day 14, AC1903 significantly reduced proteinuria and preserved the number of podocytes. Furthermore, AC1903 had no effect on blood urea nitrogen, creatinine, or body weight in Dahl S rats, nor did it alter mean arterial pressure (MAP) [1].
In AT1R Tg rats with established advanced disease (severe proteinuria >25 mg/day, ~18 weeks), twice-daily intraperitoneal injections of AC1903 (50 mg/kg) for 7 days suppressed severe proteinuria [1]. Inside-out electrophysiology measurements in isolated glomeruli from AT1R Tg rats confirmed that AC1903 blocks TRPC5 channel activity during proteinuric disease progression [1]. Morphometric analysis demonstrated that AC1903 treatment led to a significant reduction in pseudocyst formation and podocyte loss in AT1R Tg rats with advanced disease, maintaining podocyte numbers near baseline wild-type levels (~120 podocytes per glomerulus) [1]. In Dahl salt-sensitive (Dahl S) rats, a model of hypertension-induced FSGS, AC1903 (50 mg/kg twice daily i.p.) administered at the start of 2% NaCl diet (6-week-old rats, Onset) significantly reduced the rate of progressive proteinuria [1]. In Dahl S rats with more advanced disease (2% NaCl for 1 week leading to severe proteinuria), AC1903 treatment initiated on day 7 for 1 week significantly suppressed proteinuria and preserved podocyte numbers (~120 podocytes per glomerulus) compared to vehicle controls, without affecting mean arterial pressure [1]. |
| Enzyme Assay |
For whole-cell patch-clamp electrophysiology, HEK-293 cells expressing human TRPC5, TRPC4, or TRPC6 were used. Currents were elicited by application of riluzole (3 μM) for TRPC5 activation, carbachol (CCh) for TRPC4, or 1-oleoyl-2-acetyl-glycerol (OAG) for TRPC6. AC1903 was applied at concentrations ranging from 1 to 100 μM. Dose-response curves were generated to calculate half-maximal inhibitory concentrations [1].
For inside-out patch-clamp recordings from isolated rat glomeruli, podocyte membrane patches were excised. Riluzole (3 μM) was used to activate TRPC5 single-channel activity, and AC1903 was applied to assess inhibition. Open channel probability (NPo) was quantified at a holding potential of -60 mV [1]. |
| Cell Assay |
Cell Viability Assay[1]
Cell Types: Podocytes Cell Tested Concentrations: 30 µM Incubation Duration: 36 hrs (hours) Experimental Results: Rescue of podocyte death. For ROS measurement, wild-type podocytes were treated with AngII (10 μM) in the presence or absence of AC1903 (30 μM) or N-acetylcysteine (NAC). ROS levels were quantified [1]. For caAT1R experiments, podocytes were engineered to overexpress a constitutively active mutant of human AT1R (caAT1R). ROS production was measured in the presence of AC1903 (30 μM), ML204 (30 μM), or the Rac1 inhibitor NSC23677 (50 μM) [1]. For cell death assay, podocytes expressing caAT1R were treated with AC1903 (30 μM), ML204 (30 μM), or NSC23677 (50 μM). Cell death was assessed within 36 hours of caAT1R expression [1]. |
| Animal Protocol |
Animal/Disease Models: Dahl salt-sensitive rat hypertension-induced focal segmental glomerulosclerosis (FSGS) model [1]
Doses: 50 mg/kg Route of Administration: intraperitoneal (ip) injection; intraperitoneal (ip) injection. 50 mg/kg; twice (two times) daily; 7 days Experimental Results: Inhibits progression of proteinuric nephropathy by sparing podocytes. Animal/Disease Models: 6weeks old Dahl S rats were treated with 2% NaCl for 1 week and suffered from severe and progressive proteinuria [1]. Doses: 50 mg/kg. Route of Administration: intraperitoneal (ip) injection; intraperitoneal (ip) injection; intraperitoneal (ip) injection. 50 mg/kg; twice (two times) daily; starting on day 7, treatment for 1 week until day 14 Experimental Results: Taking it at the beginning of a high-salt diet diminished the incidence of proteinuria, taking it one week after starting a high-salt diet prevented progression . For AT1R Tg rats with advanced disease (severe proteinuria >25 mg/day, ~18 weeks), AC1903 was administered via intraperitoneal injection at a dose of 50 mg/kg twice daily for 7 days. Control animals received vehicle (phosphate-buffered saline or other vehicle) [1]. For Dahl salt-sensitive (Dahl S) rats, 6-week-old animals were placed on a 2% NaCl diet. In the Onset protocol, AC1903 (50 mg/kg i.p. twice daily) was initiated at the start of the high-salt diet. In the Advanced protocol, rats received 2% NaCl for 1 week to develop severe proteinuria, then AC1903 treatment (50 mg/kg i.p. twice daily) was initiated on day 7 and continued for 1 week until day 14 [1]. For inside-out electrophysiology, glomeruli were isolated from AT1R Tg rats at different disease stages (Onset ~12 weeks, Advanced ~18 weeks). Podocyte membrane patches were excised and recorded at Vm = -60 mV. Riluzole (3 μM) was applied to activate TRPC5 channels, and AC1903 was added to assess inhibition [1]. |
| Toxicity/Toxicokinetics |
In AT1R Tg rats treated with AC1903 (50 mg/kg twice daily i.p. for 7 days), no evidence of toxicity was observed (body weight, blood urea nitrogen, creatinine were unaffected; see fig. S7, A to C) [1].
In Dahl S rats, AC1903 treatment had no effect on body weight, blood urea nitrogen, or creatinine [1]. Rats treated with TRPC5 inhibitor for up to 14 days showed no detectable toxicity [1]. Mice genetically lacking TRPC5 from birth show no gross abnormalities, except for an attenuated fear response due to a developmental defect in the amygdala [1]. |
| References | |
| Additional Infomation |
AC1903 selectively blocks TRPC5 ion channels, and its therapeutic benefit is mediated by preserving podocytes and preventing podocyte loss in progressive kidney diseases such as focal segmental glomerulosclerosis (FSGS) and hypertensive proteinuric kidney disease [1].
RNA sequencing (RNA-seq) of isolated glomeruli from AC1903-treated AT1R Tg rats revealed that AC1903 targets a specific signaling network, with Gene Ontology term enrichment showing cell adhesion and integrin signaling gene sets, supporting that AC1903 fortifies the cytoskeleton, prevents pseudocysts, and promotes cell adhesion [1]. A patent application (no. 62/555,219) covering AC1903 has been filed by Partners HealthCare-Brigham and Women's Hospital, the University of Nebraska Medical Center, and the authors [1]. AC1903 is available from the corresponding author under a materials transfer agreement [1]. |
| Molecular Formula |
C19H17N3O
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|---|---|
| Molecular Weight |
303.357784032822
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| Exact Mass |
303.137
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| Elemental Analysis |
C, 75.23; H, 5.65; N, 13.85; O, 5.27
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| CAS # |
831234-13-0
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| PubChem CID |
667146
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
512.4±60.0 °C at 760 mmHg
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| Flash Point |
263.7±32.9 °C
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| Vapour Pressure |
0.0±1.3 mmHg at 25°C
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| Index of Refraction |
1.648
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| LogP |
4.23
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
23
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| Complexity |
372
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N1=C(NCC2=CC=CO2)N(CC2C=CC=CC=2)C2C1=CC=CC=2
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| InChi Key |
OECUWHDVQIITIS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H17N3O/c1-2-7-15(8-3-1)14-22-18-11-5-4-10-17(18)21-19(22)20-13-16-9-6-12-23-16/h1-12H,13-14H2,(H,20,21)
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| Chemical Name |
1-benzyl-N-(furan-2-ylmethyl)benzimidazol-2-amine
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| Synonyms |
AC1903; AC-1903; AC 1903;
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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) |
DMSO : ~100 mg/mL (~329.64 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.24 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 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 (8.24 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 | 3.2964 mL | 16.4821 mL | 32.9641 mL | |
| 5 mM | 0.6593 mL | 3.2964 mL | 6.5928 mL | |
| 10 mM | 0.3296 mL | 1.6482 mL | 3.2964 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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