Tri-substituted acylhydrazines as tertiary amide bioisosteres: HCV NS5B polymerase inhibitors

The use of a tri-substituted acylhydrazine as an isostere of a tertiary amide was explored in a series of HCV NS5B thumb site II inhibitors. Direct replacement generated an analog with similar conformational and physicochemical properties. The series was extended to produce compounds with potent bin...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2012-07, Vol.22 (13), p.4288-4292
Hauptverfasser:	Canales, Eda, Carlson, Joseph S., Appleby, Todd, Fenaux, Martijn, Lee, Johnny, Tian, Yang, Tirunagari, Neeraj, Wong, Melanie, Watkins, William J.
Format:	Artikel
Sprache:	eng
Schlagworte:	Amide bioisostere amides Amides - chemistry Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - chemical synthesis Antiviral Agents - chemistry Antiviral Agents - pharmacology binding capacity Binding Sites Biological and medical sciences Cell Line, Tumor Computer Simulation enzyme inhibitors Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology HCV Hepacivirus - enzymology Hepatitis C virus Humans Hydrazine Hydrazines - chemistry Medical sciences PDB Pharmacology. Drug treatments Physicochemical properties Protein Structure, Tertiary RNA-directed RNA polymerase Structure-Activity Relationship structure-activity relationships Thumb Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - metabolism Virus Replication - drug effects
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Zusammenfassung:	The use of a tri-substituted acylhydrazine as an isostere of a tertiary amide was explored in a series of HCV NS5B thumb site II inhibitors. Direct replacement generated an analog with similar conformational and physicochemical properties. The series was extended to produce compounds with potent binding affinities and encouraging levels of cellular potency.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2012.05.025