ChemicalBook Product Catalog Biochemical Engineering Biochemical Reagents Agonist Inhibitors TAK-441

TAK-441

Product NameTAK-441
CAS1186231-83-3
MFC28H31F3N4O6
MW576.56
EINECS
MOL File1186231-83-3.mol

Chemical Properties

Boiling point	761.6±60.0 °C(Predicted)
Density	1.40±0.1 g/cm3(Predicted)
pka	13.88±0.10(Predicted)
form	Solid
color	Off-white to light yellow

Usage And Synthesis

Uses

TAK-441 is a highly potent and orally active hedgehog (Hh) signaling inhibitor with an IC50value of 4.4 nM. TAK-441 has strong antitumor activity in solid tumors[1][2][3].

in vivo

TAK-441 (compound 11d) (oral; 10 mg/kg, 100 mg/kg) has favorable exposure and good oral absorption in BALB/c-nu/nu mice^[1].
TAK-441 (oral, 1 and 25 mg/kg, QD for 14 days) has strong antitumor activity and can achieve dose-dependent plasma and tumor concentrations by improving the solubility of TAK-441 in Ptc1^+/-p53^-/- mice bearing medulloblastoma allografts^[1].
TAK-441 (iv, 1 mg/kg; po, 10 mg/kg) is able to achieve sufficient exposure following oral administration in rats and dogs^[1].
TAK-441 (oral; 1, 10, and 25 mg/kg) shows dose-dependent antitumor activity in xenografted mice, the IC₅₀ value for the tumor growth inhibition is 0.075 mg/ml^[1].
Pharmacokinetic Parameters of TAK-441 in BALB/c-nu/nu mice (oral and Alzet infusion administration; 100 mg/kg; single)^[1].

Compd		Mouse PK 10mg/kg			Mouse PK 100mg/kg
	Cmax (lg/mL)		AUC (lgh/mL)	Cmax (lg/mL)		AUC (lgh/mL)
1	2.65		12.1	3.63		32.3
11d	5.62		28.3	21.5		206

Animal Model:

rats and dogs^[1]

Dosage:

1 mg/kg, 10 mg/kg

Administration:

iv, 1 mg/kg; po, 10 mg/kg

Result:

Compd			Mouse PK 10mg/kg
	V_ss(mL/kg)	CL (mL/h/kg)	AUC_0–24h,iv(ng h/mL)	AUC_0–24h,po(ng h/mL)	F (%)
Rat	681.6 ± 81.6	397.9 ± 10.1	2532.3 ± 69.1	8031.8 ± 1218.6	31.7
Dog	2181.3 ± 82.8	161.3 ± 35.6	5101.5 ± 685.5	45405.6 ± 5812.0	90.3 ± 8.8

Animal Model:	BALB/c-nu/nu mice^[1]
Dosage:	10 mg/kg, 100 mg/kg
Administration:	oral; 10 mg/kg, 100 mg/kg
Result:	Inhibits Gli1 mRNA in the tumor and skin with IC₅₀ values of 0.0457 mg/mL and 0.113 mg/mL, respectively.

Animal Model:	Ptc1^+/-p53^-/- mice^[1]
Dosage:	1 and 25 mg/kg
Administration:	oral, 1 and 25 mg/kg, QD for 14 days
Result:	Showed strong antitumor activity and resulted in a dose-dependent PK profile by improving solubility.

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 DOI:10.1016/j.bmc.2012.07.034
[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 DOI:10.1124/dmd.112.049650
[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. DOI:10.1002/ijc.28193

Preparation Products And Raw materials

TAK-441 Supplier

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