Synonym
PF-06446846 hydrochloride; PF-06446846 HCl; PF-06446846; PF 06446846; PF06446846; PF-6446846; PF 6446846; PF6446846;
IUPAC/Chemical Name
N-(3-Chloropyridin-2-yl)-N-((3R)-piperidin-3-yl)-4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)benzamide hydrochloride
InChi Key
AQSJYIVIWBIHOU-UNTBIKODSA-N
InChi Code
InChI=1S/C22H20ClN7O.ClH/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;1H/t17-;/m1./s1
SMILES Code
O=C(N(C1=NC=CC=C1Cl)[C@H]2CNCCC2)C3=CC=C(N4N=NC5=CC=CN=C54)C=C3.[H]Cl
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO
Shelf Life
>3 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
Biological target:
PF-06446846 hydrochloride is an orally active and highly selective inhibitor of translation of Proprotein convertase subtilisin/kexin type 9 (PCSK9).
In vitro activity:
As shown in Figure 2D, PCSK9 inhibitor PF-06446846 had a clear effect on cell proliferation at 100µM concentration in HeLa, OVCAR3 and OVCAR3cis cells, whereas JHSO2 cells that do not express PCSK9 showed minimal sensitivity (85% cell survival), indicating that PCSK9 plays a survival role in these cancer cells.
Reference: Cancers (Basel). 2021 Jul 24;13(15):3727. https://pubmed.ncbi.nlm.nih.gov/34359627/
In vivo activity:
To explore the safety of the compound and to gain insight into the in vivo activity of PF-06446846, male rats were orally administered PF-06446846 at doses of 5, 15, and 50 mg/kg daily for 14 d. Dose-dependent lowering of plasma PCSK9 was observed following single and repeated dosing of PF-06446846 (Fig 2A and 2B). In addition to the reduction in circulating levels of PCSK9, evidence of inhibition of PCSK9 downstream function was observed at the 50 mg/kg dose, with a statistically significant 30% decrease in total plasma cholesterol and 58% decrease in LDL cholesterol but no significant decrease in high-density lipoprotein (HDL).
Reference: Nat Commun. 2020 Oct 2;11(1):4941. https://pubmed.ncbi.nlm.nih.gov/28323820/
|
Solvent |
mg/mL |
mM |
comments |
| Solubility |
| DMSO |
172.0 |
365.68 |
|
| Ethanol |
94.0 |
199.85 |
|
| Water |
97.0 |
206.23 |
|
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
470.36
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
1. Jacome Sanz D, Raivola J, Karvonen H, Arjama M, Barker H, Murumägi A, Ungureanu D. Evaluating Targeted Therapies in Ovarian Cancer Metabolism: Novel Role for PCSK9 and Second Generation mTOR Inhibitors. Cancers (Basel). 2021 Jul 24;13(15):3727. doi: 10.3390/cancers13153727. PMID: 34359627; PMCID: PMC8345177.
2. Li W, Chang ST, Ward FR, Cate JHD. Selective inhibition of human translation termination by a drug-like compound. Nat Commun. 2020 Oct 2;11(1):4941. doi: 10.1038/s41467-020-18765-2. PMID: 33009412; PMCID: PMC7532171.
In vitro protocol:
1. Jacome Sanz D, Raivola J, Karvonen H, Arjama M, Barker H, Murumägi A, Ungureanu D. Evaluating Targeted Therapies in Ovarian Cancer Metabolism: Novel Role for PCSK9 and Second Generation mTOR Inhibitors. Cancers (Basel). 2021 Jul 24;13(15):3727. doi: 10.3390/cancers13153727. PMID: 34359627; PMCID: PMC8345177.
2. Li W, Chang ST, Ward FR, Cate JHD. Selective inhibition of human translation termination by a drug-like compound. Nat Commun. 2020 Oct 2;11(1):4941. doi: 10.1038/s41467-020-18765-2. PMID: 33009412; PMCID: PMC7532171.
In vivo protocol:
1. Li W, Chang ST, Ward FR, Cate JHD. Selective inhibition of human translation termination by a drug-like compound. Nat Commun. 2020 Oct 2;11(1):4941. doi: 10.1038/s41467-020-18765-2. PMID: 33009412; PMCID: PMC7532171.
1. Lintner NG, McClure KF, Petersen D, Londregan AT, Piotrowski DW, Wei L, Xiao J, Bolt M, Loria PM, Maguire B, Geoghegan KF, Huang A, Rolph T, Liras S, Doudna JA, Dullea RG, Cate JH. Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain. PLoS Biol. 2017 Mar 21;15(3):e2001882. doi: 10.1371/journal.pbio.2001882. Erratum in: PLoS Biol. 2018 Apr 17;16(4):e1002628. doi: 10.1371/journal.pbio.1002628. PMID: 28323820; PMCID: PMC5360235.
2. Londregan AT, Wei L, Xiao J, Lintner NG, Petersen D, Dullea RG, McClure KF, Bolt MW, Warmus JS, Coffey SB, Limberakis C, Genovino J, Thuma BA, Hesp KD, Aspnes GE, Reidich B, Salatto CT, Chabot JR, Cate JHD, Liras S, Piotrowski DW. 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. doi: 10.1021/acs.jmedchem.8b00650. Epub 2018 Jun 25. PMID: 29878763.
