Document Detail

Conformation-based restrictions and scaffold replacements in the design of hepatitis C virus polymerase inhibitors: discovery of deleobuvir (BI 207127).
MedLine Citation:
PMID:  24159919     Owner:  NLM     Status:  MEDLINE    
Conformational restrictions of flexible torsion angles were used to guide the identification of new chemotypes of HCV NS5B inhibitors. Sites for rigidification were based on an acquired conformational understanding of compound binding requirements and the roles of substituents in the free and bound states. Chemical bioisosteres of amide bonds were explored to improve cell-based potency. Examples are shown, including the design concept that led to the discovery of the phase III clinical candidate deleobuvir (BI 207127). The structure-based strategies employed have general utility in drug design.
Steven R LaPlante; Michael Bös; Christian Brochu; Catherine Chabot; René Coulombe; James R Gillard; Araz Jakalian; Martin Poirier; Jean Rancourt; Timothy Stammers; Bounkham Thavonekham; Pierre L Beaulieu; George Kukolj; Youla S Tsantrizos
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Publication Detail:
Type:  Journal Article     Date:  2013-11-11
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  57     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2014 Mar 
Date Detail:
Created Date:  2014-03-13     Completed Date:  2014-05-15     Revised Date:  2014-05-21    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1845-54     Citation Subset:  IM    
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MeSH Terms
Antiviral Agents / chemistry,  pharmacology*
Benzimidazoles / chemistry,  pharmacology*
Crystallography, X-Ray
Drug Design*
Enzyme Inhibitors / chemistry,  pharmacology*
Hepacivirus / drug effects*,  enzymology
Indoles / chemistry,  pharmacology*
Magnetic Resonance Spectroscopy
Models, Molecular
Molecular Conformation
Viral Nonstructural Proteins / antagonists & inhibitors*
Reg. No./Substance:
0/Antiviral Agents; 0/Benzimidazoles; 0/Enzyme Inhibitors; 0/Indoles; 0/NS-5 protein, hepatitis C virus; 0/Viral Nonstructural Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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