TAK-441

Names

[ Name ]:
TAK-441

[Synonym ]:
s-Triazine,4,6-bis(isopropylamino)-2-ethyl
6-ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide
2-Ethyl-4,6-bis(iso-propylamino)-s-triazine
2-ethyl-4,6-bis(isopropylamino)-1,3,5-triazine
[11] 6-Ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide
6-ethyl-N,N'-diisopropyl-[1,3,5]triazine-2,4-diamine
4,6-Bis(isopropylamino)-2-ethyl-s-triazine
1H-Pyrrolo[3,2-c]pyridine-2-carboxamide, 6-ethyl-4,5-dihydro-N-[1-(2-hydroxyacetyl)-4-piperidinyl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-
6-Ethyl-N-(1-glycoloyl-4-piperidinyl)-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide
6-ethyl-N,N'-di(propan-2-yl)-1,3,5-triazine-2,4-diamine

Biological Activity

[Description]:

TAK-441 (compound 11d) is a highly potent and oral hedgehog (Hh) signaling inhibitor with an IC50value of 4.4 nM. TAK-441 (compound 11d) has strong antitumor activity in solid tumors[1].

[Related Catalog]:

Research Areas >> Cancer

Signaling Pathways >> Stem Cell/Wnt >> Hedgehog

[Target]

IC50: 4.4 nM (Gli-luc reporter)[1]

[In Vitro]

TAK-441 (compound 11d) has potent activity in the Gli-luc reporter with an IC50 value of 4.4 nM and good solubility. TAK-441 inhibits Gli1 mRNA with IC50 values of 0.0457 and 0.113 mg/ml in the tumor and skin, respectively. TAK-441 does not affect androgen withdrawal-induced Shh up-regulation orviability of LNCaP cells. TAK-441 leads to delayed castration-resistant progression of LNCaP xenografts by disrupting paracrine Hh signaling with the tumor stroma[1][2][3]. Cell Viability Assay[1] Cell Line: NIH3T3/Gli-luc cells Concentration: 0.03–1000 nM Incubation Time: 48 h Result: Showed acceptable solubility and potent Hh inhibitory activity. Cell Viability Assay[3] Cell Line: LNCaP cells Concentration: 0.5-500 nM Incubation Time: 48-72 h Result: Did not affect up-regulation of Shh of in vitro viability of LNCaP cells under androgen-deprivedconditionsin. Western Blot Analysis[3] Cell Line: LNCaP, C4-2, DU145 and PC3 cells Concentration: Incubation Time: Result: Reflected androgen-responsive PCa and express both Shh and Dhh in LNCaP and C4-2 cells and reflect restricted Shh expression of CRPC in DU145 and PC3 cells.

[References]

[1]. Tomohiro Ohashi, et al. Discovery of the investigational drug TAK-441, a pyrrolo[3,2-c]pyridine derivative, as a highly potent and orally active hedgehog signaling inhibitor: modification of the core skeleton for improved solubility. Bioorg Med Chem. 2012 Sep 15;20(18):5507-17.

[2]. Akifumi Kogame, et al. Pharmacokinetic and pharmacodynamic modeling of hedgehog inhibitor TAK-441 for the inhibition of Gli1 messenger RNA expression and antitumor efficacy in xenografted tumor model mice. Drug Metab Dispos

[3]. Naokazu Ibuki, et al. TAK-441, a novel investigational smoothened antagonist, delays castration-resistant progression in prostate cancer by disrupting paracrine hedgehog signaling. Int J Cancer. 2013 Oct 15;133(8):1955-66.

Chemical & Physical Properties

[ Density]:
1.4±0.1 g/cm3

[ Boiling Point ]:
761.6±60.0 °C at 760 mmHg

[ Molecular Formula ]:
C₂₈H₃₁F₃N₄O₆

[ Molecular Weight ]:
576.564

[ Flash Point ]:
414.4±32.9 °C

[ Exact Mass ]:
576.219543

[ PSA ]:
126.36000

[ LogP ]:
2.64

[ Vapour Pressure ]:
0.0±2.7 mmHg at 25°C

[ Index of Refraction ]:
1.606

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

Related Compounds

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