کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1375140 | 981932 | 2010 | 5 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
The introduction of P4 substituted 1-methylcyclohexyl groups into Boceprevir®: A change in direction in the search for a second generation HCV NS3 protease inhibitor
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موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
In the search for a second generation HCV protease inhibitor, molecular modeling studies of the X-ray crystal structure of Boceprevir® 1 bound to the NS3 protein suggest that expansion into the S4 pocket could provide additional hydrophobic Van der Waals interactions. Effective replacement of the P4 tert-butyl with a cyclohexylmethyl ligand led to inhibitor 2 with improved enzyme and replicon activities. Subsequent modeling and SAR studies led to the pyridine 38 and sulfone analogues 52 and 53 with vastly improved PK parameters in monkeys, forming a new foundation for further exploration.
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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 20, Issue 8, 15 April 2010, Pages 2617–2621
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 20, Issue 8, 15 April 2010, Pages 2617–2621
نویسندگان
Frank Bennett, Yuhua Huang, Siska Hendrata, Raymond Lovey, Stephane L. Bogen, Weidong Pan, Zhuyan Guo, Andrew Prongay, Kevin X. Chen, Ashok Arasappan, Srikanth Venkatraman, Francisco Velazquez, Latha Nair, Mousumi Sannigrahi, Xiao Tong, John Pichardo,