| Size | Price | Stock | Qty |
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| Targets |
The primary target is renin, an aspartyl protease that catalyzes the rate-limiting step in the RAAS cascade by cleaving angiotensinogen to angiotensin I. SPH3127 is a direct renin inhibitor (DRI) with an IC50 of 0.4 nM for recombinant human renin and 0.45 nM for human plasma renin activity. Additionally, the compound inhibits sphingosine kinase 1 (SK1), which modulates sphingolipid metabolism and has potential therapeutic applications in cancer, autoimmune diseases, and inflammation.
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| ln Vitro |
SPH3127 is a potent direct renin inhibitor with IC50 values of 0.4 nM for recombinant human renin and 0.45 nM for human plasma renin activity. The compound also shows activity as a sphingosine kinase 1 (SK1) inhibitor, modulating sphingolipid metabolism and reducing tumor growth by altering the balance of sphingolipid signaling. This dual activity makes SPH3127 a versatile research tool for both cardiovascular and cancer research.
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| ln Vivo |
SPH3127 (oral; 0-10 mg/kg; once) showed good absorption in cynomolgus monkeys [1]. SPH3127 (orally; 0-3 mg/kg; once) showed antihypertensive effects in Tsukuba hypertensive mice [1].
SPH3127 shows anti-hypertensive effects in animal models. In the Tsukuba hypertensive mouse model (which expresses human renin and angiotensinogen genes), SPH3127 administered orally at 0-3 mg/kg once daily demonstrated significant blood pressure lowering effects, with efficacy comparable to or better than existing antihypertensive agents. The compound is in clinical development for hypertension, with a maximum clinical trial phase of III across all indications, and has 4 investigational indications. |
| Enzyme Assay |
The direct renin inhibition assay is performed using recombinant human renin or human plasma as the enzyme source. Renin (e.g., 0.1 nM final concentration) is incubated with its substrate angiotensinogen (or a synthetic peptide substrate such as Mca-RPKPVE-F-Nal-RK(Dnp)-OH) in assay buffer (50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 0.1 mg/mL BSA). Varying concentrations of SPH3127 (0.01-100 nM) are added, and the reaction is allowed to proceed at 37degC for 60-90 minutes. The amount of angiotensin I produced is quantified by radioimmunoassay (RIA) or by measuring fluorescence (Ex/Em = 320/405 nm for Mca-labeled substrates). The IC50 is calculated from the dose-response curve.
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| Cell Assay |
A cellular assay for renin inhibition is not directly relevant, as renin is produced in the juxtaglomerular cells of the kidney and acts in plasma. The in vivo efficacy of renin inhibitors is assessed through blood pressure measurement and plasma renin activity (PRA) assays. PRA is measured by collecting plasma from treated animals, incubating it with exogenous angiotensinogen (or relying on endogenous angiotensinogen), and quantifying angiotensin I generation by RIA or ELISA. A reduction in PRA indicates successful renin inhibition. For SK1 inhibition, cellular assays are performed in cancer cell lines (e.g., breast, colon) to measure sphingosine-1-phosphate (S1P) levels and cell viability.
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| Animal Protocol |
Animal/Disease Models: Cynomolgus monkeys were pretreated with a low-sodium diet and furosemide [1]
Doses: 0, 1, 3, 10 mg/kg Route of Administration: po (po (oral gavage)) 1, 3 and 10 mg/kg; Experimental Results: inhibit plasma renin activity, IC50 value is 0.46 nM, and have blood pressure lowering effect. Animal/Disease Models: Tsukuba hypertensive mouse (THM) [1] Doses: 0, 0.3, 1 or 3 mg/kg Route of Administration: oral; Route of Administration: oral. 0, 0.3, 1 or 3 mg/kg; Experimental Results: 0.3~3mg/kg demonstrated a dose-dependent antihypertensive effect on Tsukuba hypertensive mice, and the maximum antihypertensive effect 2~3h after any dose was administered was about 30mmHg. In the Tsukuba hypertensive mouse model (a double-transgenic mouse expressing human renin and human angiotensinogen genes), male mice (8-12 weeks old) with established hypertension are used. SPH3127 is administered via oral gavage at doses of 0.3, 1, and 3 mg/kg as a single dose. Blood pressure is measured by the tail-cuff method at baseline and at various time points (1, 3, 6, 9, 24 hours) post-administration. Plasma samples are collected to measure plasma renin activity (PRA) and angiotensin I/II levels by radioimmunoassay. In long-term studies, the compound may be administered daily for 2-4 weeks. |
| ADME/Pharmacokinetics |
As an orally active direct renin inhibitor, SPH3127 is designed for once-daily oral dosing. Specific quantitative PK parameters for the compound are not detailed; however, its classification as an oral, small-molecule DRI indicates favorable oral bioavailability and sufficient half-life to support once-daily administration. Aliskiren, the only approved DRI, has a long half-life (~24 hours) and poor bioavailability (~2.5%). SPH3127 likely improves upon these properties.
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| Toxicity/Toxicokinetics |
SPH3127 is in clinical development for hypertension, with a maximum clinical trial phase of III. Phase I and II trials are typically required to evaluate safety, tolerability, and efficacy in hypertensive patients. As a direct renin inhibitor, class-related side effects may include diarrhea, cough, headache, and angioedema, though DRIs generally have a better tolerability profile than ACE inhibitors or ARBs. Detailed toxicological data from pre-clinical studies would be available but are not published in the search results.
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| References | |
| Additional Infomation |
SPH3127 is an advanced clinical-stage compound that has progressed to Phase III clinical trials for hypertension. Direct renin inhibitors represent the most selective approach to blocking the RAAS, as renin acts at the first and rate-limiting step of the cascade. SPH3127 may offer advantages over ACE inhibitors and ARBs by reducing angiotensin I formation, thereby decreasing angiotensin II and aldosterone levels while preventing angiotensin II “escape” seen with ACE inhibitors. As of the latest updates, SPH3127 is an investigational drug and has not yet been approved for sale.
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| Molecular Formula |
C22H32N6O4
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| Molecular Weight |
444.53
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| Exact Mass |
444.248
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| CAS # |
1399849-02-5
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| Related CAS # |
2102663-60-3 (malate);1399849-02-5;
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| PubChem CID |
117877477
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| Appearance |
Off-white to pink solid powder
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| LogP |
0.8
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
32
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| Complexity |
662
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| Defined Atom Stereocenter Count |
2
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| SMILES |
C1(CC1)N(C([C@H]1CNCCO1)=O)[C@H](C)C1C2=C(N(N=1)CCCNC(=O)OC)N=C(C=C2)C
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| InChi Key |
GRTDDIZIUSADLD-CRAIPNDOSA-N
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| InChi Code |
InChI=1S/C22H32N6O4/c1-14-5-8-17-19(26-27(20(17)25-14)11-4-9-24-22(30)31-3)15(2)28(16-6-7-16)21(29)18-13-23-10-12-32-18/h5,8,15-16,18,23H,4,6-7,9-13H2,1-3H3,(H,24,30)/t15-,18-/m1/s1
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| Chemical Name |
methyl N-[3-[3-[(1R)-1-[cyclopropyl-[(2R)-morpholine-2-carbonyl]amino]ethyl]-6-methylpyrazolo[3,4-b]pyridin-1-yl]propyl]carbamate
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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 (~224.96 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (11.25 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 50.0 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: ≥ 5 mg/mL (11.25 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 50.0 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. View More
Solubility in Formulation 3: ≥ 5 mg/mL (11.25 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2496 mL | 11.2478 mL | 22.4957 mL | |
| 5 mM | 0.4499 mL | 2.2496 mL | 4.4991 mL | |
| 10 mM | 0.2250 mL | 1.1248 mL | 2.2496 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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