کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10585139 | 981362 | 2012 | 11 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
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
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کلمات کلیدی
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: 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 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](/preview/png/10585139.png)
چکیده انگلیسی
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 Cmax 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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 20, Issue 18, 15 September 2012, Pages 5507-5517
Journal: Bioorganic & Medicinal Chemistry - Volume 20, Issue 18, 15 September 2012, Pages 5507-5517
نویسندگان
Tomohiro Ohashi, Yuya Oguro, Toshio Tanaka, Zenyu Shiokawa, Yuta Tanaka, Sachio Shibata, Yoshihiko Sato, Hiroko Yamakawa, Harumi Hattori, Yukiko Yamamoto, Shigeru Kondo, Maki Miyamoto, Mitsuhiro Nishihara, Yoshimasa Ishimura, Hideaki Tojo, Atsuo Baba,