کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10594149 | 981818 | 2011 | 5 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Impact of passive permeability and gut efflux transport on the oral bioavailability of novel series of piperidine-based renin inhibitors in rodents
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موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
An oral bioavailability issue encountered during the course of lead optimization in the renin program is described herein. The low Fpo of pyridone analogs was shown to be caused by a combination of poor passive permeability and gut efflux transport. Substitution of pyridone ring for a more lipophilic moiety (log D >1.7) had minimal effect on rMdr1a transport but led to increased passive permeability (Papp >10 Ã 10â6 cm/s), which contributed to overwhelm gut transporters and increase rat Fpo. Log D and in vitro passive permeability determination were found to be key in guiding SAR and improve oral exposure of renin inhibitors.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 21, Issue 18, 15 September 2011, Pages 5547-5551
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 21, Issue 18, 15 September 2011, Pages 5547-5551
نویسندگان
Jean-François Lévesque, Kelly Bleasby, Amandine Chefson, Austin Chen, Daniel Dubé, Yves Ducharme, Pierre-André Fournier, Sébastien Gagné, Michel Gallant, Erich Grimm, Michael Hafey, Yongxin Han, Robert Houle, Patrick Lacombe, Sébastien Laliberté,