TAK-441 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 | | | | Vss(mL/kg) | CL (mL/h/kg) | AUC0–24h,iv(ng h/mL) | AUC0–24h,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