کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1371571 981849 2010 5 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
An in situ oxidation strategy towards overcoming hERG affinity
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
An in situ oxidation strategy towards overcoming hERG affinity
چکیده انگلیسی

In an effort to overcome hERG affinity with a lead compound, several S-oxide and N-oxide analogues were synthesised with a much improved hERG profile but low in vivo absorption. This led to the implementation of an in situ oxidation strategy wherein a sulfide was dosed orally and systemic levels of the corresponding sulfoxide and sulfone were monitored. SAR and pharmacokinetic data to support this as a possible strategy are presented, although ultimately the approach was shown not to be suitable due to very low levels of active circulating metabolites.

A series of oxidised, for example, sulfoxide, CCR5 antagonists have been identified as highly potent with a large window over inhibition of the hERG channel, but with very low permeability and in vivo absorption. A strategy is described which involved dosing to rats a much more permeable sulfide precursor, which underwent in situ oxidation to the corresponding sulfoxide and sulfone. SAR, metabolism and pharmacokinetic data which underpinned this strategy is described.Figure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 20, Issue 22, 15 November 2010, Pages 6400–6404
نویسندگان
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