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
2012
Ohashi, Tomohiro | Oguro, Yuya | Tanaka, Toshio | Shiokawa, Zenyu | Tanaka, Yuta | Shibata, Sachio | Sato, Yoshihiko | Yamakawa, Hiroko | Hattori, Harumi | Yukiko, Yamamoto | Kondo, Shigeru | Miyamoto, Maki | Nishihara, Mitsuhiro | Ishimura, Yoshimasa | Tojo, Hideaki | Baba, Atsuo | Sasaki, Satoshi
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 (100mg/kg) revealed the Cₘₐₓ value 3.63μg/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.
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