期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 20, 期 18, 页码 5507-5517出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2012.07.034
关键词
Hedgehog; Hh signaling inhibitor; Pyrrolo[3,2-c]pyridine-4-one; TAK-441
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 mu g/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. (C) 2012 Elsevier Ltd. All rights reserved.
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