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| Targets |
Tissue-Nonspecific Alkaline Phosphatase (TNAP): SBI-425 is a potent inhibitor of TNAP with IC50 = 0.016 μM in the PPi assay and IC50 = 0.105 μM in the whole blood assay (pNPP substrate). [1]
Selectivity against other alkaline phosphatases: SBI-425 is highly selective (>80 μM) against intestinal alkaline phosphatase (IAP) and placental alkaline phosphatase (PLAP). [1] |
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| ln Vitro |
In the spleenocytes of mice with CLP injuries, administration of SBI-425 has been shown to suppress Foxp3 expression in CD4+ and CD8+ T cells [3].
TNAP Enzyme Inhibition (PPi Assay): SBI-425 demonstrated potent inhibition of TNAP with IC50 = 0.016 μM in the standard assay measuring pyrophosphorolysis rate toward native substrate PPi. [1] TNAP Enzyme Inhibition (Whole Blood Assay): SBI-425 showed strong activity in the in situ whole blood assay (measuring activity in minimally diluted blood plasma samples) with IC50 = 0.105 μM using pNPP as substrate. This represents a minimal potency shift compared to earlier compounds in the series. [1] Selectivity Panel: SBI-425 was tested in a Eurofins/Ricerca Hit Profiling screen against 35 targets at 10 μM and showed no cross-reactivity, with the exception of modest activity against CYP3A4 (>30 μM). [1] Comparison with Earlier Compounds: Unlike previous TNAP inhibitors (e.g., compound 1 with IC50 <20 nM in PPi assay but >5 μM in whole blood assay), SBI-425 maintained excellent potency in the more physiologically relevant whole blood assay. [1] |
| ln Vivo |
1.19 SBI-425 mouse PK parameters [1] SBI-425 Clp Compound (mL/min/kg) 5.14 volts per kilogram 1.03 Cmax (μg/mL) 178 AUC (μg*hr/mL) 848 t1/2 (hour) 2.3% of F 58.
TNAP Inhibition in Mouse Plasma: Following a single oral dose of 10 mg/kg SBI-425 in mice, TNAP activity in plasma was inhibited >75% out to 8 hours and approximately 50% at 24 hours post-dose (Figure 2). [1] Efficacy in Disease Models: The compound has demonstrated activity in blocking calcification in patient-derived fibroblasts as well as in rodent models of GACI (generalized arterial calcification of infancy) and PXE (pseudoxanthoma elasticum), as referenced in the paper. [1] |
| Enzyme Assay |
Standard TNAP Assay (PPi): TNAP activity was measured using pyrophosphate (PPi) as the native substrate. IC50 values were determined for inhibition of pyrophosphorolysis. [1]
Whole Blood TNAP Assay (pNPP): An in situ biomarker assay was developed measuring TNAP activity in minimally diluted blood plasma samples using p-nitrophenyl phosphate (pNPP) as substrate. This assay simulates the compound environment in vivo to more accurately predict the level of TNAP inhibition in vivo. IC50 values were determined in this assay as a critical secondary screen. [1] Selectivity Assays: Inhibition of intestinal alkaline phosphatase (IAP) and placental alkaline phosphatase (PLAP) was measured to determine selectivity, with IC50 values >80 μM for SBI-425 against these isozymes. [1] |
| Cell Assay |
Primary Brain Microvascular Endothelial Cell Culture: BMECs were isolated from adult male mice, cultured on collagen-coated plates, and treated with puromycin to obtain pure cultures. Cells were seeded onto E-Plates for impedance measurement. [3]
Barrier Function Assay: Real-time changes in barrier function were quantified by measuring cellular impedance using an xCelligence RTCA DP system. Cells reached confluence (~25 hours after seeding), then were treated with: vehicle (DMSO 0.3%), SBI-425 (100 μM), IFN-γ (10 ng/mL) + TNF-α (10 ng/mL), or SBI-425 + IFN-γ + TNF-α. Cell index was recorded continuously for ~96 hours at 15-minute intervals. Data were normalized and slopes calculated over 24-hour intervals. [3] Cytotoxicity Assessment: Cytotoxicity was assessed in separate experiments to confirm no significant differences in cell viability with treatments. [3] Gene Expression Analysis: BMECs were plated in 24-well dishes, treated for 24 hours, and total RNA isolated using RNeasy Mini Kit. Quantitative real-time PCR was performed using Taqman assays for mouse Alpl and 18S rRNA (housekeeping). Fold changes were calculated using the 2^-ΔΔCt method. [3] |
| Animal Protocol |
Pharmacokinetic Studies:** Rodent pharmacokinetics were examined for SBI-425 (compound 27) and analogs 32 and 33. Dosing information and sample collection details are not fully described, but results are presented in Table 4. [1]
* **In Vivo TNAP Inhibition Study:** Mice were dosed orally with SBI-425 at 10 mg/kg. At various time points post-dose, blood samples were collected, and TNAP activity in plasma was measured to determine the level of inhibition. Results are shown in Figure 2, demonstrating >75% inhibition out to 8 hours and ~50% inhibition at 24 hours. [1] Pharmacokinetic Studies: Rodent pharmacokinetics were examined for SBI-425 (compound 27) and analogs 32 and 33. Dosing information and sample collection details are not fully described, but results are presented in Table 4. [1] In Vivo TNAP Inhibition Study: Mice were dosed orally with SBI-425 at 10 mg/kg. At various time points post-dose, blood samples were collected, and TNAP activity in plasma was measured to determine the level of inhibition. Results are shown in Figure 2, demonstrating >75% inhibition out to 8 hours and ~50% inhibition at 24 hours. [1] |
| ADME/Pharmacokinetics |
Rodent Pharmacokinetics: SBI-425 (compound 27) was evaluated for pharmacokinetic properties. Key parameters (from Table 4) include: very low clearance, good half-life, and excellent oral bioavailability. After a 10 mg/kg oral dose, SBI-425 displayed very high oral exposure with AUC >800 μg·h/mL. [1]
Comparison with Analogs: Compounds 32 and 33 were also evaluated and showed generally low to very low clearance, good t1/2, and good to excellent oral bioavailability. [1] |
| Toxicity/Toxicokinetics |
CYP Inhibition: SBI-425 showed modest activity against CYP3A4 (>30 μM) in a Eurofins/Ricerca Hit Profiling screen at 10 μM. No other significant cross-reactivity was observed against 35 other targets. [1]
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| References |
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| Additional Infomation |
Background: SBI-425 (5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide) is a potent and selective inhibitor of tissue-nonspecific alkaline phosphatase (TNAP). It was developed through an optimization campaign to create an orally bioavailable TNAP inhibitor with robust in vivo activity. [1]
Chemical Structure: SBI-425 features a pyridyl core with a carboxamide at the 3-position and a 5-chloro-2-methoxyphenyl sulfonamide moiety. The structure is shown in Tables 2 and 3. [1] Synthesis: SBI-425 is synthesized as shown in Scheme 1. Chloroanisole is treated with sulfuryl chloride to give sulfonyl chloride 36, which is reacted with esterified aminonicotinic acid 38, followed by amide formation with ammonium hydroxide to yield SBI-425 in good yields. The compound has been generated on >50g scale using this method. [1] Therapeutic Potential: TNAP inhibition raises extracellular pyrophosphate (ePPi) levels, which prevents pathological soft-tissue calcification. SBI-425 has potential therapeutic applications in disorders characterized by low ePPi and abnormal calcification, including chronic kidney disease-associated vascular calcification, pseudoxanthoma elasticum (PXE), generalized arterial calcification of infancy (GACI), calcification of joints and arteries (CALJA), and Hutchinson-Gilford progeria syndrome (HGPS). [1] Efficacy Data: The compound has already demonstrated activity in blocking calcification in patient-derived fibroblasts and in rodent models of GACI and PXE, as referenced in the paper. [1] Advantages over Previous Inhibitors: Unlike earlier TNAP inhibitors that showed a large potency shift between standard enzyme assays and whole blood assays, SBI-425 maintains excellent potency in the physiologically relevant whole blood assay (only ~6-fold shift), making it a superior tool for in vivo studies. [1] |
| Molecular Formula |
C13H12CLN3O4S
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|---|---|
| Molecular Weight |
341.770080566406
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| Exact Mass |
341.023
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| CAS # |
1451272-71-1
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| PubChem CID |
89768286
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| Appearance |
White to off-white solid powder
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| LogP |
0.9
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
22
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| Complexity |
496
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| Defined Atom Stereocenter Count |
0
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| SMILES |
COC1=C(C=C(C=C1)Cl)S(=O)(=O)NC2=CN=CC(=C2)C(=O)N
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| InChi Key |
SBAITEDLNTYIOE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C13H12ClN3O4S/c1-21-11-3-2-9(14)5-12(11)22(19,20)17-10-4-8(13(15)18)6-16-7-10/h2-7,17H,1H3,(H2,15,18)
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| Chemical Name |
5-[(5-chloro-2-methoxyphenyl)sulfonylamino]pyridine-3-carboxamide
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| Synonyms |
SBI-425 SBI-425SBI-425
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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 : ~86.67 mg/mL (~253.59 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.17 mg/mL (6.35 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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 21.7 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9259 mL | 14.6297 mL | 29.2594 mL | |
| 5 mM | 0.5852 mL | 2.9259 mL | 5.8519 mL | |
| 10 mM | 0.2926 mL | 1.4630 mL | 2.9259 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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