کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1358974 981374 2011 15 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
17,20-Lyase inhibitors. Part 3: Design, synthesis, and structure–activity relationships of biphenylylmethylimidazole derivatives as novel 17,20-lyase inhibitors
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
17,20-Lyase inhibitors. Part 3: Design, synthesis, and structure–activity relationships of biphenylylmethylimidazole derivatives as novel 17,20-lyase inhibitors
چکیده انگلیسی

A novel series of biphenylylmethylimidazole derivatives and related compounds were synthesized as inhibitors of 17,20-lyase, a key enzyme in the production of steroid hormones, and their biological activities were evaluated. In an attempt to identify potent and selective inhibitors of 17,20-lyase over the related CYP3A4 enzyme, a homology model for human 17,20-lyase was developed using the X-ray crystallographic structure of the mammalian CYP2C5 enzyme. With the aid of molecular modeling, optimization of the biphenyl moiety was performed to give an acetamide derivative, which was resolved by HPLC to give the active (−)-enantiomer. The obtained active enantiomer showed not only potent inhibition of both rat and human 17,20-lyase,with IC50 values of 14 and 26 nM, respectively, but also excellent selectivity (>300-fold) for inhibition of 17,20-lyase over CYP3A4. Moreover, the active enantiomer significantly reduced both serum testosterone and DHEA concentrations in a monkey model after single oral administration. Asymmetric synthesis of the active enantiomer was also developed via a chiral intermediate using a diastereoselective Grignard reaction.

A novel series of biphenylylmethylimidazole derivatives were synthesized as inhibitors of 17,20-lyase, and their biological activities were evaluated.Figure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 19, Issue 7, 1 April 2011, Pages 2428–2442
نویسندگان
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