| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| Other Sizes |
| Targets |
PCSK9 mRNA (via RNA interference). Inclisiran is a double-stranded siRNA that binds to PCSK9 mRNA, recruiting the RNA-induced silencing complex (RISC) to degrade the mRNA and prevent PCSK9 protein synthesis.
|
|---|---|
| ln Vitro |
Inclisiran is a small RNA molecule that is double-stranded. It functions by preventing the transcription of proprotein convertase subtilisin kexin 9 (PCSK-9). This reduces the amount of PCSK-9 present in the hepatocytes, which in turn increases the expression of low-density lipoprotein (LDL) receptors in the hepatocyte membrane. Ultimately, this lowers the levels of LDL cholesterol (LDL-C) that are circulated.
Inclisiran (siRNA) binds to PCSK9 mRNA and triggers its degradation via RNA interference. This prevents translation of the PCSK9 protein. In vitro studies in hepatocytes demonstrate that Inclisiran treatment reduces PCSK9 secretion and increases LDL receptor expression on the cell surface, leading to enhanced LDL uptake and clearance. |
| ln Vivo |
In animal models and clinical trials, Inclisiran reduces circulating PCSK9 levels by 60-80% and lowers LDL cholesterol by 40-50% after a single subcutaneous injection. Dosing intervals of every 6 months provide sustained LDL-C lowering, making it a convenient lipid-lowering therapy for patients with hypercholesterolemia.
|
| Enzyme Assay |
Inclisiran is not evaluated in standard cell-free enzyme assays because its mechanism of action is RNA interference, not direct enzyme inhibition. Target engagement is instead demonstrated in hepatocyte cultures by measuring reduction in PCSK9 mRNA levels (qPCR) and PCSK9 protein secretion (ELISA).
|
| Cell Assay |
For in vitro studies, primary human hepatocytes or HepG2 cells are treated with Inclisiran (0.1-100 nM) for 24-72 hours. Total RNA is extracted for PCSK9 mRNA quantification by qRT-PCR. Conditioned media is collected for PCSK9 protein quantification by ELISA. LDL receptor expression on the cell surface can be measured by flow cytometry or Western blot.
|
| Animal Protocol |
In animal models (e.g., mice expressing human PCSK9 or non-human primates), Inclisiran is administered subcutaneously (single dose). Blood samples are collected at multiple time points (days to weeks) for measurement of plasma PCSK9 levels (ELISA) and LDL cholesterol levels (enzymatic assay). Liver PCSK9 mRNA levels are measured by qRT-PCR at sacrifice to confirm target engagement.
|
| ADME/Pharmacokinetics |
Inclisiran is administered by subcutaneous injection. It is extensively bound to plasma proteins and has a long terminal half-life (~9 days in humans). Inclisiran is metabolized by nucleases to nucleotides of various lengths. It is eliminated primarily through biliary excretion. Steady-state accumulation occurs after multiple doses.
|
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation Currently, there is no clinical information regarding the use of inclisiran during lactation. Because inclisiran is a large oligonucleotide, its concentration in breast milk may be very low, and the amount absorbed by the infant may be minimal. If the mother needs to use inclisiran, breastfeeding should not be discontinued. Until more data are available, inclisiran should be used with caution during lactation, especially when breastfeeding newborns or premature infants. ◉ Effects on Breastfed Infants As of the revision date, no relevant published information was found. ◉ Effects on Lactation and Breast Milk As of the revision date, no relevant published information was found. In clinical trials, Inclisiran has demonstrated a favorable safety and tolerability profile. The most common adverse events are mild-to-moderate injection-site reactions (pain, redness, rash), occurring in approximately 5-10% of patients. No serious liver or kidney toxicity has been observed. It has been approved by the FDA and EMA. |
| References | |
| Additional Infomation |
Cemdisiran is currently being investigated in the clinical trial NCT03841448 (a study of Cemdisiran for the treatment of adult immunoglobulin A nephropathy (Igan)). Cemdisiran is a proprietary formulation composed of a small interfering RNA (siRNA) targeting terminal complement component 5 (C5) of the complement pathway, conjugated to an N-acetylgalactosamine (GalNAc) ligand, with potential use in the treatment of complement-mediated diseases such as paroxysmal nocturnal hemoglobinuria (PNH). Following subcutaneous injection of Cemdisiran, the GalNAc ligand portion specifically binds to and is taken up by the desialylate glycoprotein receptor (ASGPR) expressed on hepatocytes. Intracellularly, the siRNA binds to C5 mRNA, thereby inhibiting the translation and expression of the C5 protein. This reduces plasma C5 levels, prevents C5 cleavage into pro-inflammatory components, and blocks complement-mediated hemolysis. C5 is a complement pathway protein highly expressed in the liver.
See also: Inclisiran (note moved to). Drug Indications Leqvio is indicated for adult patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) or mixed dyslipidemia, as an adjunct to diet: in combination with statins, or with other lipid-lowering therapies, for patients who cannot achieve their LDL-C target with the maximum tolerated dose of statins; or orally alone or in combination with other lipid-lowering therapies, for patients who are intolerant to or have contraindications to statins. Inclisiran (brand name Leqvio®) was first approved in Europe (2020) and the US (2021) for the treatment of primary hypercholesterolemia and mixed dyslipidemia as an adjunct to diet and statin therapy. It is the first and only approved siRNA therapy for lowering LDL cholesterol. CAS: 1639324-58-5, molecular weight ~16339 g/mol. |
| Molecular Formula |
C78H140N11O34P
|
|---|---|
| Molecular Weight |
1806.97328567505
|
| Exact Mass |
1805.93
|
| CAS # |
1639324-58-5
|
| PubChem CID |
126480325
|
| Appearance |
White to off-white solid powder
|
| LogP |
-8
|
| Hydrogen Bond Donor Count |
22
|
| Hydrogen Bond Acceptor Count |
34
|
| Rotatable Bond Count |
66
|
| Heavy Atom Count |
124
|
| Complexity |
2950
|
| Defined Atom Stereocenter Count |
17
|
| SMILES |
P(=O)(O)(O)OC[C@@H]1C[C@H](CN1C(CCCCCCCCCCC(NC(COCCC(NCCCNC(CCCCO[C@H]1[C@@H]([C@H]([C@H]([C@@H](CO)O1)O)O)NC(C)=O)=O)=O)(COCCC(NCCCNC(CCCCO[C@H]1[C@@H]([C@H]([C@H]([C@@H](CO)O1)O)O)NC(C)=O)=O)=O)COCCC(NCCCNC(CCCCO[C@H]1[C@@H]([C@H]([C@H]([C@@H](CO)O1)O)O)NC(C)=O)=O)=O)=O)=O)O
|
| InChi Key |
LQRNAUZEMLGYOX-LZVIIAQDSA-N
|
| InChi Code |
InChI=1S/C78H140N11O34P/c1-50(93)85-66-72(108)69(105)55(43-90)121-75(66)117-35-15-12-21-58(97)79-29-18-32-82-61(100)26-38-114-47-78(88-64(103)24-10-8-6-4-5-7-9-11-25-65(104)89-42-54(96)41-53(89)46-120-124(111,112)113,48-115-39-27-62(101)83-33-19-30-80-59(98)22-13-16-36-118-76-67(86-51(2)94)73(109)70(106)56(44-91)122-76)49-116-40-28-63(102)84-34-20-31-81-60(99)23-14-17-37-119-77-68(87-52(3)95)74(110)71(107)57(45-92)123-77/h53-57,66-77,90-92,96,105-110H,4-49H2,1-3H3,(H,79,97)(H,80,98)(H,81,99)(H,82,100)(H,83,101)(H,84,102)(H,85,93)(H,86,94)(H,87,95)(H,88,103)(H2,111,112,113)/t53-,54+,55+,56+,57+,66+,67+,68+,69-,70-,71-,72+,73+,74+,75+,76+,77+/m0/s1
|
| Chemical Name |
[(2S,4R)-1-[12-[[1,3-bis[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]-2-[[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]methyl]propan-2-yl]amino]-12-oxododecanoyl]-4-hydroxypyrrolidin-2-yl]methyl dihydrogen phosphate
|
| 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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
H2O: 5 mg/mL (0.31 mM)
|
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.5534 mL | 2.7671 mL | 5.5341 mL | |
| 5 mM | 0.1107 mL | 0.5534 mL | 1.1068 mL | |
| 10 mM | 0.0553 mL | 0.2767 mL | 0.5534 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.
VictORION-INCLUSION: Evaluating Inclisiran for Cholesterol Managment in Heart Disease
CTID: NCT06249165
Phase: Phase 4 Status: Recruiting
Date: 2024-11-21
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
