tak-441 and Disease-Models--Animal

tak-441 has been researched along with Disease-Models--Animal* in 1 studies

Other Studies

1 other study(ies) available for tak-441 and Disease-Models--Animal

Article	Year
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. Bioorganic & medicinal chemistry, 2012, Sep-15, Volume: 20, Issue:18 We recently reported the discovery of the novel pyrrolo[3,2-c]quinoline-4-one derivative 1 as a potent inhibitor of Hedgehog (Hh) pathway signaling. However, the PK evaluation of 1 at high dosage (100 mg/kg) revealed the C(max) value 3.63 μg/mL, likely due to poor solubility of this compound. Efforts to improve solubility by reducing the aromatic ring count of the core system led to N-methylpyrrolo[3,2-c]pyridine derivative 11. Further optimization of the 3-alkoxy group led to compound 11d with acceptable solubility and potent Hh inhibitory activity. Compound 11d suppressed transcription factor Gli1 mRNA expression in tumor-associated stromal tissue and inhibited tumor growth (treatment/control ratio, 3%) in a mouse medulloblastoma allograft model owing to the improved PK profile based on increased solubility. Compound 11d (TAK-441) is currently in clinical trials for the treatment of advanced solid tumors. Topics: Animals; Antineoplastic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; Hedgehog Proteins; Humans; Kruppel-Like Transcription Factors; Medulloblastoma; Mice; Mice, Nude; Models, Molecular; Molecular Structure; NIH 3T3 Cells; Pyridines; Pyrroles; RNA, Messenger; Signal Transduction; Solubility; Structure-Activity Relationship; Transplantation, Homologous; Zinc Finger Protein GLI1	2012

Article

Year

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.

Bioorganic & medicinal chemistry, 2012, Sep-15, Volume: 20, Issue:18

We recently reported the discovery of the novel pyrrolo[3,2-c]quinoline-4-one derivative 1 as a potent inhibitor of Hedgehog (Hh) pathway signaling. However, the PK evaluation of 1 at high dosage (100 mg/kg) revealed the C(max) value 3.63 μg/mL, likely due to poor solubility of this compound. Efforts to improve solubility by reducing the aromatic ring count of the core system led to N-methylpyrrolo[3,2-c]pyridine derivative 11. Further optimization of the 3-alkoxy group led to compound 11d with acceptable solubility and potent Hh inhibitory activity. Compound 11d suppressed transcription factor Gli1 mRNA expression in tumor-associated stromal tissue and inhibited tumor growth (treatment/control ratio, 3%) in a mouse medulloblastoma allograft model owing to the improved PK profile based on increased solubility. Compound 11d (TAK-441) is currently in clinical trials for the treatment of advanced solid tumors.

Topics: Animals; Antineoplastic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; Hedgehog Proteins; Humans; Kruppel-Like Transcription Factors; Medulloblastoma; Mice; Mice, Nude; Models, Molecular; Molecular Structure; NIH 3T3 Cells; Pyridines; Pyrroles; RNA, Messenger; Signal Transduction; Solubility; Structure-Activity Relationship; Transplantation, Homologous; Zinc Finger Protein GLI1

2012