| Identification | Back Directory | [Name]
PACRITINIB | [CAS]
937272-79-2 | [Synonyms]
SB1518
CS-914
PACRITINIB
Pacritinib, >=98%
SB1518(Pacritinib)
Pacritinib (SB1518)
PACRITINIB USP/EP/BP
SB1518; SB 1518; SB-1518
SB1518; SB 1518; SB-1518; PACRITINIB.
(16E)-11-[2-(1-Pyrrolidinyl)ethoxy]-14,19-dioxa-5,7,27-triazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2,4,6(27),8,10,12(26),16,21,23-decaene
14,19-Dioxa-5,7,27-triazatetracyclo[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6(27),8,10,12(26),16,21,23-decaene, 11-[2-(1-pyrrolidinyl)ethoxy]-, (16E)-
16E)-11-[2-(1-Pyrrolidinyl)ethoxy]-14,19-dioxa-5,7,27-triazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2,4,6(27),8,10,12(26),16,21,23-decaene Pacritinib (SB1518) | [Molecular Formula]
C28H32N4O3 | [MDL Number]
MFCD22572772 | [MOL File]
937272-79-2.mol | [Molecular Weight]
472.59 |
| Chemical Properties | Back Directory | [Boiling point ]
694.3±65.0 °C(Predicted) | [density ]
1.22±0.1 g/cm3(Predicted) | [storage temp. ]
Store at -20°C | [solubility ]
DMSO:5.0(Max Conc. mg/mL);10.6(Max Conc. mM) | [form ]
A crystalline solid | [pka]
9.56±0.20(Predicted) | [color ]
Light yellow to yellow | [InChIKey]
HWXVIOGONBBTBY-ONEGZZNKSA-N | [SMILES]
C12=CC(=CC=C1)COCC=CCOCC1=CC(=CC=C1OCCN1CCCC1)NC1=NC2=CC=N1 |t:10| |
| Hazard Information | Back Directory | [Description]
Pacritinib received accelerated approval in 2022 for the treatment of adults with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109 /L, which affects 26% of all myelofibrosis patients (~20,000 in the United States). Unlike several other JAK2 inhibitors, pacritinib exhibits good selectivity (~60-fold) for JAK2 over JAK1 while also inhibiting JAK3 with about 25-fold lower potency than JAK2. Pacritinib exhibits equipotent activity against FLT3 (IC50 = 22 nM) and mutant FLT3-D835Y (IC50 = 6?nM) at the same potency range as JAK2 (JAK2 IC50 = 23 nM). | [Characteristics]
Class: non-receptor tyrosine kinase (JAK3)
Treatment: myelofibrosis
Elimination half-life = 40 h
Protein binding = 99% | [Uses]
Pacritinib is a JAK2/FLT3 inhibitor used in the treatment of acute myeloid leukemia showing significant tumor growth inhibition and lung metastasis. | [Mechanism of action]
Pacritinib competes with JAK2 for ATP binding, which may result in inhibition of JAK2 activation, inhibition of the JAK-STAT signaling pathway, and so caspase-dependent apoptosis. | [Synthesis]
First, nitrophenol 33.5 was alkylated with 1,2-bromochloroethane to afford 33.6, and the aryl aldehyde was reduced using sodium borohydride to afford benzyl alcohol 33.7. The alcohol was then alkylated using allyl bromide to afford 33.8 with another terminal olefin for a ring-closing aromatization reaction. The alkyl chloride 33.8 was reacted with pyrrolidine to form the tertiary amine 33.9. Next, the nitro group was reduced using tin chloride to afford aniline 33.10. The final step was to construct the macrocycle via a SNAr reaction between aniline 33.10 and chloropyridine 33.4 and a subsequent ring-closing aromatization reaction using a Grignard second-generation catalyst and complete the synthesis of Pacritinib.
 | [Enzyme inhibitor]
This pyrimidine-based macrocycle and potent protein kinase inhibitor (FW
= 472.59 g/mol; CAS 937272-79-2; Solubility: 11 mg/mL DMSO), also
known as SB1518, selectively targets Janus Kinase 2 (or JAK2; IC50 = 23
nM) and Fms-Like Tyrosine Kinase-3 (or FLT3; IC50 = 22 nM), with values
of 1280 and 522 nM for JAK1 and JAK3. FLT3 is genetically altered in up
to 35% of acute myeloblastic leukemias, making it an attractive target for
AML patients. Pacritinib has potent anti-proliferative effects on myeloid
and lymphoid cell lines driven by mutant or wild-type JAK2 or FLT3,
resulting from cell cycle arrest and induction of apoptosis. SB1518 has
favorable pharmacokinetic properties after oral dosing in mice, is well
tolerated and significantly reduces splenomegaly and hepatomegaly in a
JAK2 (Val-617-Phe) -driven disease model. Primary Mode of Inhibitory
Action: Upregulation of JAK2 in FLT3-TKI-resistant AML cells was
identified as a potential mechanism of resistance to selective FLT3
inhibition. This resistance could be overcome by pacritinib’s combined
inhibition of FLT3 and JAK2 in this cellular model. Pacritinib potently
inhibits FLT3 auto-phosphorylation and downstream STAT5, MAPK and
PI3K signaling pathways in AML cell lines with highest potency against
cells harboring FLT3-ITD mutations. Blockade of FLT3 signaling was
also demonstrated in primary AML blasts treated ex vivo with pacritinib. In
both cell lines and primary blasts, pacritinib treatment led to the induction
of G1 arrest, inhibition of cell proliferation, as well as caspase-dependent
apoptosis. The anti-proliferative effects of pacritinib on the FLT3-ITD
harboring cell lines MV4-11 (IC50 = 47 nM) and MOLM-13 (IC50 = 67 nM),
which have been reported previously,16 are in the same range as the
inhibition of intracellular FLT3 signalling. |
|
| Company Name: |
J & K SCIENTIFIC LTD.
|
| Telephone: |
18210857532 18210857532 |
| Website: |
https://www.jkchemical.com |
| Company Name: |
Jia Xing Isenchem Co.,Ltd
|
| Telephone: |
0573-85285100 18627885956 |
| Website: |
https://www.chemicalbook.com/ShowSupplierProductsList14265/0_EN.htm |
| Company Name: |
NCE Biomedical Co.,Ltd.
|
| Telephone: |
4000-027-021 |24 +86-13986109188 | +86-15623472865 | +81-08033611988 |
| Website: |
www.chemicalbook.com/ShowSupplierProductsList15748/0_EN.htm |
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