NVP-TNKS656

NVP-TNKS656 Property

Boiling point:

700.7±70.0 °C(Predicted)

Density 

1.37±0.1 g/cm3(Predicted)

storage temp. 

Sealed in dry,Store in freezer, under -20°C

solubility 

Soluble in DMSO

form 

crystalline solid

pka

6.66±0.10(Predicted)

color 

White to light yellow

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Warning

Hazard statements

H302Harmful if swallowed

H400Very toxic to aquatic life

H410Very toxic to aquatic life with long lasting effects

Precautionary statements

P264Wash hands thoroughly after handling.

P264Wash skin thouroughly after handling.

P270Do not eat, drink or smoke when using this product.

P273Avoid release to the environment.

P301+P312IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.

P330Rinse mouth.

P391Collect spillage. Hazardous to the aquatic environment

P501Dispose of contents/container to..…

NVP-TNKS656 Chemical Properties,Usage,Production

Description

NVP-TNKS656 is an orally bioavailable inhibitor of tankyrase 2 (TNKS2; IC₅₀ = 6 nM). It is selective for TNKS2 over poly(ADP-ribose) polymerase (PARP) 1 and 2 (IC₅₀s = >19 and 32 nM, respectively). NVP-TNKS656 inhibits Wnt ligand-induced signaling with an IC₅₀ value of 3.5 nM in an HEK293 cell reporter assay. In vivo, NVP-TNKS656 (350 mg/kg) reduces Axin 2 mRNA expression, a Wnt/β-catenin target gene, in MMTV-Wnt1 tumor bearing mice.

Uses

NVP-TNKS656 is a highly potent, selective, and orally active TNKS2 inhibitor with IC50 of 6 nM, and is > 300 fold selectivity against PARP1 and PARP2.

Synthesis

Example 5: Synthesis of N-cyclopropylmethyl-2-[4-(4-methoxybenzoyl)-piperidin-1-yl]-N-(4-oxo-tetrahydro-4H-pyrano[4,3-d]pyrimidin-2-ylmethyl)-acetamide. 2-(4-(4-methoxybenzoyl)piperidin-1-yl)acetic acid (0.071 g, 0.26 mmol, 1 eq.) and N,N-diisopropylethylamine (DIEA, 0.089 mL, 0.51 mmol, 2 eq.) were dissolved in 2 mL of N,N-dimethylformamide (DMF), followed by addition of O-(7-azabenzotriazol-1-yl)-N ,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 0.107 g, 0.281 mmol, 1.1 eq.). The reaction mixture was stirred at room temperature for 30 minutes. Then, a 1 mL DMF solution of 2-[(cyclopropylmethylamino)methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (0.06 g, 0.26 mmol, 1 eq.) was added to the reaction mixture, and stirring was continued overnight at room temperature.After 18 h, the reaction mixture was diluted with 10 mL of water and dichloromethane (3 x 50 mL) was used for Extraction. The organic phases were combined, concentrated and purified by preparative high performance liquid chromatography (HPLC, 20-100% acetonitrile/water, 10 min, containing 0.1% trifluoroacetic acid, SunFire C18 OBD 50x50mm column at a flow rate of 60 mL/min) to afford the target compound N-(cyclopropylmethyl)-2-(4-(4-methoxybenzoyl)piperidin-1-yl)- N-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)acetamide as a white solid (0.03 g, 24% yield).1H NMR (400 MHz, methanol-d4) δ ppm 7.94-8.07 (m, 2H), 6.98-7.10 (m, 2H), 4.64-4.70 (m, 1H), 4.54-4.60 (m, 1H), 4.44-4.52 (m, 2H), 4.28-4.37 (m, 1H), 3.94-3.99 (m, 1H), 3.91-3.95 (m, 2H), 3.88 (s, 3H), 3.67-3.80 (m, 2H), 3.40-3.61 (m, 1H). 3.33-3.40 (m, 2H), 3.09-3.27 (m, 2H), 2.50-2.72 (m, 2H), 1.92-2.26 (m, 4H), 0.83-1.15 (m, 1H), 0.12-0.67 (m, 4H). High resolution mass spectrometry (HRMS) calculated value C27H35N4O5 [M+H]+ 495.2607, measured value 495.2606. mass spectrometry (ESI) m/z 495.3 ([M+H]+). Retention time: 2.89 min (5-75% acetonitrile/water, 7.75 min with 0.1% formic acid, Inertsil ODS3 100x3mm C18 column, flow rate 1.0 mL/min).

in vitro

the ic50 value of nvp-tnks656 against parp1, tnks2, parp2, and stf was > 19, 0.006, 32, and 0.0035 μm, respectively [1].

in vivo

the clearance and volume of distribution of nvp-tnks656 were 10 ml/min/kg and 0.6 l/kg after intravenous administration in mice. the exposure and oral bioavailability was 32% and 53%, respectively. in the mouse mammary tumor virus (mmtv)-wnt1 transgenic model, oral administration of nvp-tnks656 (350 mg/kg) activated the wnt signaling over a 24-h time course. nvp-tnks656 treatment reduced the wnt/beta-catenintarget gene axin2 mrna level by 70-80% [1].

IC 50

TNKS2: 6 nM (IC₅₀); PARP2: 32 μM (IC₅₀)

References

shultz m d, cheung a k, kirby c a, et al. identification of nvp-tnks656: the use of structure-efficiency relationships to generate a highly potent, selective, and orally active tankyrase inhibitor[j]. journal of medicinal chemistry, 2013, 56(16): 6495-6511.