Pomalidomide CAS 19171-19-8

Introduction：Basic information about Pomalidomide CAS 19171-19-8, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.

Pomalidomide Basic information

• Product Name: Pomalidomide
• Synonyms: 4-Amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione;Pomalidomide;Pomalidomide(CC-4047);ActiMid;CC-4047;4-AMino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;1H-Isoindole-1,3(2H)-dione,4-aMino-2-(2,6-dioxo-3-piperidinyl)-;Pomalidomide(CC-4047,Actimid)
• CAS: 19171-19-8
• MF: C13H11N3O4
• MW: 273.24
• EINECS: 805-902-5
• Product Categories: Inhibitor;Inhibitors;CC-4047
• Mol File: 19171-19-8.mol

Pomalidomide Chemical Properties

• Melting point: 318.5 - 320.5°
• Boiling point: 582.9±45.0 °C(Predicted)
• density: 1.570±0.06 g/cm3(Predicted)
• storage temp.: 2-8°C
• solubility: DMSO: ≥14mg/mL
• pka: 10.75±0.40(Predicted)
• form: powder
• color: yellow
• Merck: 14,135
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 1 month.
• InChI: InChI=1S/C13H11N3O4/c14-7-3-1-2-6-10(7)13(20)16(12(6)19)8-4-5-9(17)15-11(8)18/h1-3,8H,4-5,14H2,(H,15,17,18)
• InChIKey: UVSMNLNDYGZFPF-UHFFFAOYSA-N
• SMILES: C1(=O)C2=C(C(N)=CC=C2)C(=O)N1C1CCC(=O)NC1=O

Safety Information

• WGK Germany: 3
• RTECS: NR3397905
• HS Code: 29251900
• Storage Class: 6.1C - Combustible acute toxic Cat.3 toxic compounds or compounds which causing chronic effects
• Hazard Classifications: Repr. 1B
• Hazardous Substances Data: 19171-19-8(Hazardous Substances Data)

Pomalidomide Usage And Synthesis

Description

Pomalidomide inhibits LPS-induced TNF-α release with IC50 of 13 nM in PBMCs.

In vitro

Pomalidomide inhibits lipopolysaccharide (LPS) stimulated TNF-alpha release in human PBMC and in human whole blood with IC50 values of 13 nM and 25 nM, respectively. Pomalidomide inhibits the growth of T regulatory cells which is stimulated by IL-2 with an IC50 of ~1 μM. Treatment with Pomalidomide (6.4 nM-10 μM) increases the production of IL-2 in human peripheral blood T cells, and is slightly more potent in the CD4+ subset than in the CD8+ subset. Pomalidomide is significantly more potent than CC-5013 at elevating IL-2, IL-5, and IL-10 levels, but only slightly more potent than CC-5013 at elevating IFN-γ levels.
Pomalidomide enhances SEE and Raji cells induced AP-1 transcriptional activity in Jurkat cells in a dose-dependent manner, with a maximal enhancement of 4-fold at 1 μM. Exposure of Raji cells to various concentrations of Pomalidomide (2.5-40 μg/mL) for 48 hours leads to a significant decrease in cell proliferation and DNA synthesis. There is a reduction of ~40% compared to vehicle-treated controls.

In vivo

Pomalidomide enhances the antitumor effect of rituximab against B-cell lymphomas in severe combined immunodeficient mice. Administration of Pomalidomide in combination with rituximab, gives the mice a median survival period of 74 days compared with 58 days of CC5013/rituximab treatment and 45 days of rituximab nonotherapy. The synergistic effect of Pomalidomide and rituximab can be completely abrogated by depletion of NK cells, supporting the proposal that NK cell expansion is one mechanism by which Pomalidomide may augment rituximab antitumor activity.

Description

In February 2013, the US FDA approved pomalidomide (also known as CC4047) for the treatment of multiple myeloma (MM) in patients with disease progression after receiving other cancer therapeutics. Pomalidomide is a 4-amino analog of thalidomide with enhanced potency and an improved toxicity profile. Pomalidomide and thalidomide exert their effects by modulation of immunity, inhibition of angiogenesis, interference with the bone/tumor microenvironment, and inhibition of the cereblon protein. Pomalidomide potently inhibited in vitro proliferation in a variety of human MM cell lines, IC₅₀～10 nM, while thalidomide showed almost no inhibition up to 100 μM. In mouse MM tumor models, 50 mg/kg daily doses of pomalidomide resulted in marked inhibition of tumor growth after 15 days of treatment and complete regression in 3–6 weeks versus thalidomide-treated controls at the same dose. Pomalidomide is prepared by condensation of 4-nitrophthalic anhydride with 3-aminopiperidine-2,6-dione followed by catalytic hydrogenation of the nitro group.

Chemical Properties

Yellow Solid

Originator

Celgene Corporation (United States)

History

Pomalidomide, a third-generation immunomodulatory agent (IMiD) following thalidomide and lenalidomide, was developed by Celgene in the United States. It represents a structural optimization and enhanced potency of thalidomide-like drugs. Its development stems from precise modifications to the thalidomide structure, particularly the addition of an amino group at the fourth carbon atom of the phthalimide ring. This improvement enhances its antitumor activity and immunomodulatory effects, aiming to overcome patient resistance to the first two generations of IMiD drugs. Pomalidomide exerts its potent anti-myeloma effect by binding to the intracellular Cerebrolysin (CRBN) protein and targeting the degradation of various tumor proteins. Its key clinical approval was based on the results of the MM-003 Phase III clinical trial, which showed that pomalidomide in combination with low-dose dexamethasone (Pom+LoDEX) significantly prolonged progression-free survival (PFS) in patients with relapsed and refractory multiple myeloma (RRMM). Based on this groundbreaking data, the U.S. FDA granted accelerated approval to pomalidomide on February 8, 2013, for the treatment of patients with RRMM who have received at least two prior lines of therapy, making it an important third- or fourth-line treatment option for refractory myeloma. Subsequently, its indication was expanded to include Kaposi's sarcoma in 2020. However, due to its structural similarity to thalidomide, pomalidomide remains subject to strict risk assessment and remission strategy (REMS) procedures worldwide to ensure its safety.

Uses

Pomalidomide inhibits LPS-induced TNF-α release with IC50 of 13 nM

Uses

Pomalidomide is a thalidomide derivative, a potent inhibitor of TNF-α production. It is an antiinflammatory and antitumor agent used in the treatment of multiple myeloma.

Uses

Pomalidomide is a second generation immunomodulator, TNF-α inhibitor, and thalidomide analog. An inhibitor of LPS-induced TNFαrelease.

Definition

ChEBI: Pomalidomide is an aromatic amine that is thalidomide substituted at position 4 on the isoindole ring system by an amino group. Used for the treatment of multiple myeloma in patients who failed to respond to previous therapies. It has a role as an antineoplastic agent, an immunomodulator and an angiogenesis inhibitor. It is a dicarboximide, a member of isoindoles, a member of piperidones and an aromatic amine. It is functionally related to a thalidomide.

Brand name

Pomalyst

reaction suitability

reagent type: ligand

Biochem/physiol Actions

Pomalidomide is an effective fetal hemoglobin (HbF) inducer that downregulates the key γ-globin repressors, SRY-box transcription factor 6 (SOX6), and BAF chromatin remodeling complex subunit (BCL11A).

Clinical Use

Treatment of multiple myeloma

Synthesis

First, condensation of commercially available 3-nitrophthalicanhydride (133) and L-glutamine in warm DMF gave nitrophthalimide134. Although the authors from Celgene do notexplicitly describe the racemization of the stereocenter derivedfrom L-glutamine, scrambling of the stereocenter has beenreported during this step under neutral conditions at elevatedtemperatures. Next, hydrogenative reduction of the nitro groupfurnished the anilinophthalimide 135, and this was followed bytreatment with CDI in refluxing acetonitrile to secure the piperidonedione and ultimately furnish pomalidomide (XVIII) as theracemate in 87% overall yield from 134.

target

TNF-α

Drug interactions

Potentially hazardous interactions with other drugs
Antidepressants: concentration increased by fluvoxamine.

Metabolism

Mainly metabolised in the liver by the cytochrome P450 isoenzymes CYP1A2 and CYP3A4, with CYP2C19 and CYP2D6 playing a minor role.
Following a single oral administration of [14C]-pomalidomide (2 mg) to healthy subjects, approximately 73% and 15% of the radioactive dose was eliminated in urine and faeces, respectively, with approximately 2% and 8% of the dosed radiocarbon eliminated as pomalidomide in urine and faeces.

storage

Store at +4°C

References

1) A LOPEZ-GIRONA. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide[J]. Leukemia, 2012, 26 11: 2326-2335. DOI:10.1038/leu.2012.119.
2) Zhu?et al.?(2013),?Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma; Leukemia Lymphoma,?54?683
3) KATHERINE A DONOVAN. Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome.[J]. eLife, 2018. DOI:10.7554/eLife.38430.
4) Winter?et al.?(2015),?DRUG DEVELOPMENT. Phthalimide conjunction as a strategy for in vivo target protein degradation; Science,?348?1376
5) JASMIN LOHBECK Aubry K M. Practical synthesis of a phthalimide-based Cereblon ligand to enable PROTAC development[J]. Bioorganic & Medicinal Chemistry Letters, 2016, 26 21: Pages 5260-5262. DOI:10.1016/j.bmcl.2016.09.048.

Pomalidomide Preparation Products And Raw materials

• Raw materials: 2H-Isoindole-2-carboxylic acid, 4-amino-1,3-dihydro-1,3-dioxo-, ethyl ester-->2,6-Dioxopiperidine-3-ammonium chloride-->3-aminopiperidine-2,6-dione-->2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione-->3-AMINOPHTHALIC ACID HYDROCHLORIDE-->1,1'-Carbonyldiimidazole-->Palladium-->Activated carbon-->N,N-Dimethylformamide-->Hydrogen