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J Med Chem. 2014 Mar 13;57(5):1845-54. doi: 10.1021/jm4011862. Epub 2013 Nov 11.

Conformation-based restrictions and scaffold replacements in the design of hepatitis C virus polymerase inhibitors: discovery of deleobuvir (BI 207127).

Author information

1
Departments of Chemistry and Biological Sciences, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Quebec, Canada H7S 2G5.

Abstract

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.

PMID:
24159919
DOI:
10.1021/jm4011862
[Indexed for MEDLINE]

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