کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10585164 | 981362 | 2012 | 7 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Riluzole prodrugs for melanoma and ALS: Design, synthesis, and in vitro metabolic profiling
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موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
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چکیده انگلیسی
Riluzole (1) is an approved therapeutic for the treatment of ALS and has also demonstrated anti-melanoma activity in metabotropic glutamate GRM1 positive cell lines, a mouse xenograft assay and human clinical trials. Highly variable drug exposure following oral administration among patients, likely due to variable first pass effects from heterogeneous CYP1A2 expression, hinders its clinical use. In an effort to mitigate effects of this clearance pathway and uniformly administer riluzole at efficacious exposure levels, several classes of prodrugs of riluzole were designed, synthesized, and evaluated in multiple in vitro stability assays to predict in vivo drug levels. The optimal prodrug would possess the following profile: stability while transiting the digestive system, stability towards first pass metabolism, and metabolic lability in the plasma releasing riluzole. (S)-O-Benzyl serine derivative 9 was identified as the most promising therapeutically acceptable prodrug.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 20, Issue 18, 15 September 2012, Pages 5642-5648
Journal: Bioorganic & Medicinal Chemistry - Volume 20, Issue 18, 15 September 2012, Pages 5642-5648
نویسندگان
Mark E. McDonnell, Matthew D. Vera, Benjamin E. Blass, Jeffrey C. Pelletier, Richard C. King, Carmen Fernandez-Metzler, Garry R. Smith, Jay Wrobel, Suzie Chen, Brian A. Wall, Allen B. Reitz,