| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
PCSK9 (C-terminal domain, Kd < 200 nM). PCSK9-IN-12 is a heteroaryl compound that binds to a distinct pocket in the PCSK9 C-terminal domain, blocking lysosomal trafficking of PCSK9-LDLR complexes.
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| ln Vitro |
Compound 458B, or PCSK9-IN-12, exhibits affinity for PCSK9 with a Kd value of less than 200 nM[1].
In cell-free binding assays, PCSK9-IN-12 binds to recombinant PCSK9 protein with high affinity (Kd < 200 nM). It does not disrupt the interaction between PCSK9 and LDLR. Instead, it inhibits the trafficking of PCSK9-LDLR complexes to lysosomes, preventing LDLR degradation and thereby increasing LDLR surface expression. |
| ln Vivo |
In animal studies, PCSK9-IN-12 is orally active and effectively lowers LDL cholesterol levels in hyperlipidemic animal models. By preventing PCSK9-induced LDLR degradation, it increases LDL receptor levels on hepatocytes, leading to enhanced clearance of LDL cholesterol from the bloodstream and reducing atherosclerotic plaque burden.
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| Enzyme Assay |
For binding assays (non-cellular), recombinant PCSK9 protein is immobilized on a sensor chip or in a microplate. Varying concentrations of PCSK9-IN-12 (1-1000 nM) are added, and binding affinity (Kd) is measured using surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC). For mechanism studies, PCSK9-LDLR complex formation can be assessed by co-immunoprecipitation.
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| Cell Assay |
For cellular assays, hepatocytes (primary or HepG2 cells) are treated with PCSK9 (to induce LDLR degradation) and PCSK9-IN-12 (0.1-10 microM) for 6-24 hours. LDLR protein levels are quantified by Western blot or flow cytometry. LDL uptake is measured by incubating cells with fluorescently labeled LDL (Dil-LDL) followed by fluorescence detection.
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| Animal Protocol |
PCSK9-IN-12 is administered orally to animal models (e.g., hyperlipidemic mice or non-human primates). Doses typically range from 1-30 mg/kg daily. Blood samples are collected to measure plasma LDL cholesterol levels (enzymatic assay) and PCSK9 levels (ELISA). Liver tissue is harvested at sacrifice to assess LDLR protein levels and PCSK9-LDLR complex trafficking by immunofluorescence or subcellular fractionation.
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| ADME/Pharmacokinetics |
PCSK9-IN-12 is orally bioavailable with good exposure. Pharmacokinetic studies in preclinical species have demonstrated that it binds to PCSK9 with high affinity (Kd < 200 nM) and has a favorable half-life supporting once-daily oral dosing. Detailed human PK data are available from clinical trials. Preclinical ADME profiles are consistent with oral drug development.
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies for PCSK9-IN-12 are likely completed as part of clinical development, though specific data are not widely published. As a research compound, it should be handled with standard laboratory precautions. Clinical safety data are expected from ongoing development programs for hypercholesterolemia.
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| References | |
| Additional Infomation |
Laroprovstat is a small molecule drug. The molecular weight of the monoisotope of laroprovstat is 414.16 Da.
PCSK9-IN-12 (CAS: 2455427-91-3) has the molecular formula C20H20F2N6O2 and molecular weight 414.41. It is a small-molecule PCSK9 inhibitor with a novel mechanism that does not block PCSK9-LDLR binding. It is a promising candidate for hypercholesterolemia, distinct from injectable PCSK9 antibodies and siRNA therapeutics. |
| Molecular Formula |
C20H20F2N6O2
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|---|---|
| Molecular Weight |
414.408610343933
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| Exact Mass |
414.161
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| CAS # |
2455427-91-3
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| PubChem CID |
154653847
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
3.4
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
30
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| Complexity |
641
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| Defined Atom Stereocenter Count |
2
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| SMILES |
C1(=O)N(C2=CC=C(N[C@H]3CC[C@H](NC4=NC=C(OC(F)F)C=N4)C3)N=C2)C=CC=C1
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| InChi Key |
NCHUWRLOTSAFFN-KBPBESRZSA-N
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| InChi Code |
InChI=1S/C20H20F2N6O2/c21-19(22)30-16-11-24-20(25-12-16)27-14-5-4-13(9-14)26-17-7-6-15(10-23-17)28-8-2-1-3-18(28)29/h1-3,6-8,10-14,19H,4-5,9H2,(H,23,26)(H,24,25,27)/t13-,14-/m0/s1
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| Chemical Name |
1-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]pyridin-3-yl]pyridin-2-one
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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 (241.31 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.03 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 (6.03 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 25.0 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: ≥ 2.5 mg/mL (6.03 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 | 2.4131 mL | 12.0653 mL | 24.1307 mL | |
| 5 mM | 0.4826 mL | 2.4131 mL | 4.8261 mL | |
| 10 mM | 0.2413 mL | 1.2065 mL | 2.4131 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.
Link: https://clinicaltrials.gov/ct2/show/NCT07000123
Conditions:Cardiovascular DiseaseLink: https://clinicaltrials.gov/ct2/show/NCT07000136
Conditions:Heterozygous Familial HypercholesterolaemiaLink: https://clinicaltrials.gov/ct2/show/NCT07423598
Conditions:Healthy Participants
Title:A Study to Assess the Effect of AZD0780 on the Pharmacokinetics of AZD4954 and Vice Versa in Healthy Adults
Status:Recruiting
updateDate:2026-04-22
Ctid:NCT07513571
Link: https://clinicaltrials.gov/ct2/show/NCT07513571
Conditions:Healthy ParticipantsLink: https://clinicaltrials.gov/ct2/show/NCT06834932
Conditions:DyslipidaemiaLink: https://clinicaltrials.gov/ct2/show/NCT07000357
Conditions:Cardiovascular DiseaseLink: https://clinicaltrials.gov/ct2/show/NCT07218900
Conditions:DyslipidaemiaLink: https://clinicaltrials.gov/ct2/show/NCT06692764
Conditions:Atherosclerotic Cardiovascular DiseaseLink: https://clinicaltrials.gov/ct2/show/NCT07216131
Conditions:Healthy ParticipantsLink: https://clinicaltrials.gov/ct2/show/NCT06173570
Conditions:DyslipidemiaLink: https://clinicaltrials.gov/ct2/show/NCT06742853
Conditions:DyslipidemiaLink: https://clinicaltrials.gov/ct2/show/NCT05817461
Conditions:Cardiovascular DiseasesLink: https://clinicaltrials.gov/ct2/show/NCT05787002
Conditions:DyslipidemiaLink: https://clinicaltrials.gov/ct2/show/NCT06671405
Conditions:DyslipidaemiaLink: https://clinicaltrials.gov/ct2/show/NCT06592482
Conditions:Renal ImpairmentLink: https://clinicaltrials.gov/ct2/show/NCT06576765
Conditions:Hepatic ImpairmentLink: https://clinicaltrials.gov/ct2/show/NCT05384262
Conditions:DyslipidemiaProducts are for research use only; We do not sell to patients
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