کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10582565 | 981052 | 2013 | 39 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Synthesis and evaluation of novel orally active p53-MDM2 interaction inhibitors
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موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
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چکیده انگلیسی
We have discovered and reported potent p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold. Our lead showed strong activity in vitro, but did not exhibit antitumor efficacy in vivo for the low metabolic stability. In order to obtain orally active compounds, we executed further optimization of our lead by the improvement of physicochemical properties. Thus we furnished optimal compounds by introducing an alkyl group onto the pyrrolidine at the C-2 substituent to prevent the metabolism; and modifying the terminal substituent of the proline motif improved solubility. These optimal compounds exhibited good PK profiles and significant antitumor efficacy with oral administration on a xenograft model using MV4-11 cells having wild type p53.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 21, Issue 14, 15 July 2013, Pages 4319-4331
Journal: Bioorganic & Medicinal Chemistry - Volume 21, Issue 14, 15 July 2013, Pages 4319-4331
نویسندگان
Masaki Miyazaki, Hiroyuki Naito, Yuuichi Sugimoto, Keisuke Yoshida, Haruko Kawato, Tooru Okayama, Hironari Shimizu, Masaya Miyazaki, Mayumi Kitagawa, Takahiko Seki, Setsuko Fukutake, Yoshinobu Shiose, Masashi Aonuma, Tsunehiko Soga,