کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10594684 | 981836 | 2012 | 7 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Synthesis and structure-activity relationships of dual PI3K/mTOR inhibitors based on a 4-amino-6-methyl-1,3,5-triazine sulfonamide scaffold
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کلمات کلیدی
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: Synthesis and structure-activity relationships of dual PI3K/mTOR inhibitors based on a 4-amino-6-methyl-1,3,5-triazine sulfonamide scaffold Synthesis and structure-activity relationships of dual PI3K/mTOR inhibitors based on a 4-amino-6-methyl-1,3,5-triazine sulfonamide scaffold](/preview/png/10594684.png)
چکیده انگلیسی
Phosphoinositide 3-kinase (PI3K) is an important target in oncology due to the deregulation of the PI3K/Akt signaling pathway in a wide variety of tumors. A series of 4-amino-6-methyl-1,3,5-triazine sulfonamides were synthesized and evaluated as inhibitors of PI3K. The synthesis, in vitro biological activities, pharmacokinetic and in vivo pharmacodynamic profiling of these compounds are described. The most promising compound from this investigation (compound 3j) was found to be a pan class I PI3K inhibitor with a moderate (>10-fold) selectivity over the mammalian target of rapamycin (mTOR) in the enzyme assay. In a U87 MG cellular assay measuring phosphorylation of Akt, compound 3j displayed low double digit nanomolar IC50 and exhibited good oral bioavailability in rats (Foral = 63%). Compound 3j also showed a dose dependent reduction in the phosphorylation of Akt in a U87 tumor pharmacodynamic model with a plasma EC50 = 193 nM (91 ng/mL).
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 22, Issue 17, 1 September 2012, Pages 5714-5720
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 22, Issue 17, 1 September 2012, Pages 5714-5720
نویسندگان
Ryan P. Wurz, Longbin Liu, Kevin Yang, Nobuko Nishimura, Yunxin Bo, Liping H. Pettus, Sean Caenepeel, Daniel J. Freeman, John D. McCarter, Erin L. Mullady, Tisha San Miguel, Ling Wang, Nancy Zhang, Kristin L. Andrews, Douglas A. Whittington, Jian Jiang,