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 binding affinities and encouraging levels of cellular potency.
Medicinal Chemistry Department, Gilead Sciences, 333 Lakeside Dr, Foster City, CA 94404, United States. eda.canales@gilead.com
Eda
E
Canales
Joseph S
JS
Carlson
Todd
T
Appleby
Martijn
M
Fenaux
Johnny
J
Lee
Yang
Y
Tian
Neeraj
N
Tirunagari
Melanie
M
Wong
William J
WJ
Watkins
D000577:Amides / Q000737:chemistry*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D006834:Hydrazines / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
D000577:Amides; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D006834:Hydrazines; D017361:Viral Nonstructural Proteins; C029424:hydrazine; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase