| Size | Price | |
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| 10mg | ||
| 25mg | ||
| 50mg | ||
| 100mg | ||
| 250mg |
Purity: ≥98%
PF‑06446846 (PF06446846; PF‑6446846) is a novel and potent PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor that inhibits the translation of PCSK9 by inducing the ribosome to stall around codon, mediated by the sequence of the nascent chain within the exit tunnel. PF-06446846 reduces plasma PCSK9 and total cholesterol levels in rats following oral dosing. PF-06446846 is highly selective for the inhibition of PCSK9 translation. Inhibiting PCSK9 can potentiate CD8 + T cell antitumor activity by promoting LDLR-mediated TCR recycling and signaling. Thus PCSK9/LDLR may serve as a potential target for cancer immunotherapy as well.
| ln Vitro |
PF-06446846 suppresses Huh7 cells from secreting PCSK9, with an IC50 of 0.3 μM[1]. PCSK9(1-35)-luciferase expression is inhibited by PF-06446846, with an IC50 of 2 μM[1]. Rat bone marrow and human CD34+ toxicity are demonstrated by PF-06446846 (compound 7f) [2].
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| ln Vivo |
In vivo, PF-06446846 lowers total plasma cholesterol and circulating PCSK9 levels without appearing to be harmful [1].
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| Cell Assay |
Cytotoxicity assay[2]
Cell Types: rat myeloid lineage(−) cells and CD34+ cells Tested Concentrations: 0-20 µM Incubation Duration: 72 hrs (hours) Experimental Results: demonstrated cytotoxicity against rat Lin(−) with an IC50 value of 2.9 µM and 2.7 µM and human CD34+, respectively. |
| Animal Protocol |
Animal/Disease Models: Male SD (SD (Sprague-Dawley)) (Crl:CD [SD] rats, 5 per group; 6-8 weeks old at start of dosing) [1]
Doses: 5, 15, and 50 mg/kg Route of Administration: Every Daily oral administration for 14 days. Experimental Results: Reduce plasma PCSK9, plasma total cholesterol and LDL-C (low-density lipoprotein cholesterol) in a dose-dependent manner without obvious toxicity. |
| References |
[1]. Nathanael G Lintner, et al. Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain. PLoS Biol. 2018 Apr 17;16(4):e1002628.
[2]. Allyn T. Londregan, et al. Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents. J Med Chem. 2018 Jul 12;61(13):5704-5718. |
| Molecular Formula |
C22H20CLN7O
|
|---|---|
| Molecular Weight |
433.893502235413
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| CAS # |
1632250-49-7
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| Related CAS # |
PF-06446846 hydrochloride;1632250-50-0
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| SMILES |
O=C(N(C1=NC=CC=C1Cl)[C@H]2CNCCC2)C3=CC=C(N4N=NC5=CC=CN=C54)C=C3
|
| InChi Key |
FDTXHWQFIXYHCL-QGZVFWFLSA-N
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| InChi Code |
InChI=1S/C22H20ClN7O/c23-18-5-2-12-25-20(18)29(17-4-1-11-24-14-17)22(31)15-7-9-16(10-8-15)30-21-19(27-28-30)6-3-13-26-21/h2-3,5-10,12-13,17,24H,1,4,11,14H2/t17-/m1/s1
|
| Chemical Name |
(R)-4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-N-(3-chloropyridin-2-yl)-N-(piperidin-3-yl)benzamide
|
| Synonyms |
PF‑06446846; PF-6446846; PF6446846; PF 06446846; PF06446846;
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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 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.) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3047 mL | 11.5237 mL | 23.0473 mL | |
| 5 mM | 0.4609 mL | 2.3047 mL | 4.6095 mL | |
| 10 mM | 0.2305 mL | 1.1524 mL | 2.3047 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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