| Size | Price | Stock | Qty |
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| 5mg |
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| Targets |
The compound targets PCSK9 protein synthesis, not the PCSK9-LDLR interaction. Following conversion by liver carboxylesterase 1 (CES1) to its active zwitterionic form, the active drug selectively inhibits PCSK9 translation, thereby lowering PCSK9 protein levels and influencing LDL receptor (LDLR) regulation. This mechanism is distinct from that of other PCSK9 inhibitors that block the PCSK9-LDLR interaction.
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| ln Vitro |
In human intestinal cells and hepatocytes, the CLint values of PF-06815345 hydrochloride (Example 7) (1-30 μM; 5-1440 minutes) are <82.9 μL/min/mg and 97.6 μL/min/mg, respectively [2].
PF-06815345 inhibits PCSK9 translation with an IC50 of 13.4 uM in vitro, with selectivity (4.95 to >27-fold) over off-target proteins including CDH1, HSD17B11, PCBP2, RPL27, and BCAP31. In humanized PCSK9 mice, oral administration significantly lowers plasma PCSK9 levels. The active form reaches high concentrations in hepatocytes (33.9 ug/mL in mice 0.5 hour post-dose at 300 mg/kg p.o.), with the human CES1 isoform being primarily responsible for conversion. |
| ln Vivo |
PF-06815345 hydrochloride (Example 7) (100-500 mg/kg; method; single dosage) decreases PCSK9 levels in a humanized PCSK9 mouse model. After 4 hours of therapy, skeletal PCSK9 was lowered by 72% at a dose of 500 mg/kg [2].
PF-06815345 HCl effectively lowers plasma PCSK9 in humanized PCSK9 mice (by 26%, 42%, and 53% at 5 hours post-dose following 100, 300, and 500 mg/kg oral doses). At 500 mg/kg, plasma PCSK9 is reduced by 72% 4 hours after treatment. The compound is well tolerated in rats and monkeys in vivo. PF-06815345 HCl (300 mg/kg p.o.) achieves a liver active drug concentration of 33.9 ug/mL in mice 0.5 hour post-dose. It is important to note that PF-06815345 is not active in non-humanized wild-type rodents as it requires human PCSK9. |
| Enzyme Assay |
Biochemical activity is measured by its ability to inhibit PCSK9 translation in cell-free translation systems. Recombinant or cell-extract translation machinery is incubated with human PCSK9 mRNA in the presence of varying concentrations of PF-06815345 (after conversion to its active form). Protein synthesis is monitored by incorporation of radiolabeled methionine or by a luciferase reporter.
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| Cell Assay |
PCSK9 protein levels are measured by Western blot in human hepatoma cell lines (e.g., HepG2 or Huh-7). Cells are treated with PF-06815345 HCl (1-100 uM) for 24-48 hours. After treatment, cells are lysed, and PCSK9 protein in lysates and culture media is quantified by Western blot using specific anti-PCSK9 antibodies. Secreted PCSK9 in supernatants is also measured by ELISA. LDLR levels on the cell surface are assessed by flow cytometry using LDLR-specific antibodies.
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| Animal Protocol |
In a humanized PCSK9 mouse model (mice transgenic for human PCSK9), male mice (8-10 weeks old) are administered PF-06815345 HCl via oral gavage at doses of 100-500 mg/kg (single dose). Blood samples are collected at various time points (0.5, 1, 2, 4, 8, 24 hours). Plasma PCSK9 levels are measured by ELISA, and plasma cholesterol levels are analyzed enzymatically. Liver tissue is collected for PCSK9 mRNA and protein quantification.
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| ADME/Pharmacokinetics |
PF-06815345 is an orally available prodrug with high liver specificity. Following oral administration, it is converted by liver carboxylesterase 1 (CES1) to its zwitterionic active form. In mice, a 300 mg/kg oral dose achieves a liver active drug concentration of 33.9 ug/mL at 0.5 hour, whereas in monkeys, a 30 mg/kg oral dose achieves 9.0 ug/mL. The compound is inactive in wild-type rodents, making humanized PCSK9 mice essential for efficacy studies.
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| Toxicity/Toxicokinetics |
PF-06815345 has been evaluated in rats and monkeys and is reported to be well tolerated at doses tested (up to 500 mg/kg in mice). A Phase 1 clinical trial (NCT02728544) in healthy subjects was terminated, although specific reasons for termination are not publicly detailed. As a PCSK9 inhibitor class, potential safety concerns include injection site reactions (for injectable biologics), though for this oral small molecule, liver-specific toxicity and gastrointestinal effects are typical areas of monitoring.
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| References |
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| Additional Infomation |
PF-06815345 HCl is a research-grade compound, distinct from the injectable PCSK9 monoclonal antibodies (e.g., alirocumab, evolocumab) and siRNA therapeutics (inclisiran) that are clinically approved. It represents a novel oral approach to PCSK9 inhibition via inhibition of protein synthesis rather than protein-protein interaction blockade. A Phase 1 study has been conducted, but development status is not currently active. The compound is only available for research applications.
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| Molecular Formula |
C27H30CL2FN9O4
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|---|---|
| Molecular Weight |
634.489406108856
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| Exact Mass |
633.178
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| CAS # |
2334434-49-8
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| Related CAS # |
PF-06815345;1900686-46-5
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| PubChem CID |
168006835
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
43
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| Complexity |
927
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CN1N=CC(C2C=CC(C(=O)N([C@H]3CNCCC3)C3N=CC=CC=3Cl)=CC=2F)=C1C1=NN=NN1[C@H](C)OC(=O)OCC.Cl
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| InChi Key |
RFEUFHPTEFEGDQ-KUGOCAJQSA-N
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| InChi Code |
InChI=1S/C27H29ClFN9O4.ClH/c1-4-41-27(40)42-16(2)38-25(33-34-35-38)23-20(15-32-36(23)3)19-10-9-17(13-22(19)29)26(39)37(18-7-5-11-30-14-18)24-21(28)8-6-12-31-24/h6,8-10,12-13,15-16,18,30H,4-5,7,11,14H2,1-3H31H/t16-,18+/m0./s1
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| Chemical Name |
(S)-1-(5-(4-(4-((3-chloropyridin-2-yl)((R)-piperidin-3-yl)carbamoyl)-2-fluorophenyl)-1-methyl-1H-pyrazol-5-yl)-1H-tetrazol-1-yl)ethyl ethyl carbonate hydrochloride
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| Synonyms |
PF06815345 HClPF 06815345 HClPF-06815345 HClPF-06815345 hydrochloride
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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, 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)
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| Solubility (In Vitro) |
DMSO : ~50 mg/mL (~78.80 mM)
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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.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5761 mL | 7.8803 mL | 15.7607 mL | |
| 5 mM | 0.3152 mL | 1.5761 mL | 3.1521 mL | |
| 10 mM | 0.1576 mL | 0.7880 mL | 1.5761 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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