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
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Synthesis and evaluation of novel orally active p53-MDM2 interaction inhibitors
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
نویسندگان
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