7-methyl-2-(morpholin-4-yl)-9-[1-(phenylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one

• ChemBase ID: 72553
• Molecular Formular: C21H24N4O2
• Molecular Mass: 364.44086
• Monoisotopic Mass: 364.18992603
• SMILES: c1c(cc(c2n1c(=O)cc(n2)N1CCOCC1)C(C)Nc1ccccc1)C
• Canonical SMILES: Cc1cc(C(Nc2ccccc2)C)c2n(c1)c(=O)cc(n2)N1CCOCC1
• InChI: InChI=1S/C21H24N4O2/c1-15-12-18(16(2)22-17-6-4-3-5-7-17)21-23-19(13-20(26)25(21)14-15)24-8-10-27-11-9-24/h3-7,12-14,16,22H,8-11H2,1-2H3
• InChIKey: CPRAGQJXBLMUEL-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 7-methyl-2-(morpholin-4-yl)-9-[1-(phenylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one
• IUPAC Traditional name: 7-methyl-2-(morpholin-4-yl)-9-[1-(phenylamino)ethyl]pyrido[1,2-a]pyrimidin-4-one
• Synonyms: TGX-221

Database IDs

• CAS Number: 663619-89-4
• PubChem SID: 162037478
• PubChem CID: 9907093

CALCULATED PROPERTIES

• H Acceptors: 5
• H Donor: 1
• LogD (pH = 5.5): 2.3551164
• LogD (pH = 7.4): 2.3730776
• Log P: 2.3733115
• Molar Refractivity: 117.832 cm^3
• Polarizability: 39.946083 Å^3
• Polar Surface Area: 57.17 Å^2
• Rotatable Bonds: 4
• Lipinski's Rule of Five: true

PROPERTIES

Physical Property

• Solubility: DMSO

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: PI3K

Product Information

• Salt Data: Free Base

DETAILS

Selleck Chemicals - S1169

Research Area

• Description: Cancer

Biological Activity

• Description: TGX-221 is a potent, selective PI3K inhibitor for p110β with IC50 of 8.5 nM.
• Targets: p110β
• IC50: 8.5 nM ^[1]
• In Vitro: The activity of TGX-221 against different isoforms is measured in an in vitro PI3K assay using multiple preparations of recombinant p85/p110. TGX-221 show slow potent to p110δ with IC50 of 211 nM. Furthermore, TGX-221 partially attenuates insulin-induced phosphorylation of Ser^473 of PKB in J774.2 macrophage cells. ^[1] TGX-221 inhibits platelet-ECC interaction, platelet aggregation and platelet-granulocyte binding in an extracorporeal circulation (ECC) model. ^[2] A recent study shows that after treatment with TGX-221 (0.2, 2, and 20 μM), PC3 cells show inhibition of proliferation with a significant reduction of the activity of the p110β PI3K isoform. ^[3]
• In Vivo: As an anti-thrombotic agent, TGX-221 at doses 1 + 1 (49 ± 13.9%) and 3+3 (88 ± 10.6%) improves integrated blood flow over 30 minutes in a mouse model. In addition, Tail bleeding time (BT) (sec) increases with TGX-221 doses of 3 + 3 (median 1560) and 1 + 1 (1305) and mean renal BT (sec) also increases in all TGX-221 groups. ^[4]

Protocol

• Protocol: Kinase Assay ^[1]
• Lipid kinase activity: IC50 values are measured using a standard lipid kinase activity with PI as a substrate. (i)100 μM cold ATP is used instead of 10 μM, (ii) the DMSO concentration is 1%, and (iii) [γ-^33P]ATP is used instead of [γ-^32P]ATP. The TLC plates are quantified using a phosphorimager screen. The reported IC50 values are determined by non-linear regression analysis on the basis of at least three independent experiments repeated across multiple preparations of recombinant protein.
• Protocol: Cell Assay ^[3]
• Cell Lines: PC3 cells
• Concentrations: ~20 μM
• Incubation Time: 24-72 hours
• Methods: For measurement of proliferation, cells are seeded in triplicate in 96-well culture plates and incubated overnight to allow cell attachment. The cells are incubated with TGX-221 for 24, 48, and 72 hours. At designated time intervals, cells are quantified by a crystal violet staining-based colorimetric assay. Briefly, cells are fixed by addition of 100 μl of 2.5% glutaraldehyde solution and incubated at room temperature for 30 minutes. Plates are washed three times by submersion in PBS solution. Plates are air-dried and stained by addition of 100 μL of 0.1% solution of crystal violet dissolved in deionized water and incubated for 20 minutes at room temperature, excess dye is removed by extensive washing with deionized water, and plates are air-dried prior to bound dye solubilization in 100 μL of 10% acetic acid. The optical density of dye extracts is measured directly in plates using a microplate reader at 570 nm.
• Protocol: Animal Study ^[3]
• Animal Models: FeCl3-induced arterial thrombosis in mice
• Formulation: TGX-221 is dissolved in 10% ethanol, 10% cremaphor, 10% N,N-dimethylacetamine, 70% distilled water.
• Doses: 0.3 + 0.3, 1 + 1, 3 + 3 mg/kg + mg/kg/hour
• Administration: Administered via i.v.

References

• References: [1] Chaussade C, et al. Biochem J. 2007, 404(3), 449-458.
• References: [2] Straub A, et al. Thromb Haemost. 2008, 99(3), 609-615.
• References: [3] Lu XY, et al. Appl Microbiol Biotechnol. 2011, 89(5), 1423-1433.
• References: [4] Bird JE, et al. Thromb Res. 2011, 127(6), 560-564.

REFERENCES

• Lu XY, et al. Appl Microbiol Biotechnol. 2011, 89(5), 1423-1433.
• Bird JE, et al. Thromb Res. 2011, 127(6), 560-564.
• Chaussade C, et al. Biochem J. 2007, 404(3), 449-458.
• Straub A, et al. Thromb Haemost. 2008, 99(3), 609-615.