Discovery of a novel series of potent non-nucleoside inhibitors of hepatitis C virus NS5B.
Hepatitis C virus (HCV) is a major global public health problem. While the current standard of care, a direct-acting antiviral (DAA) protease inhibitor taken in combination with pegylated interferon and ribavirin, represents a major advancement in recent years, an unmet medical need still exists for treatment modalities that improve upon both efficacy and tolerability. Toward those ends, much effort has continued to focus on the discovery of new DAAs, with the ultimate goal to provide interferon-free combinations. The RNA-dependent RNA polymerase enzyme NS5B represents one such DAA therapeutic target for inhibition that has attracted much interest over the past decade. Herein, we report the discovery and optimization of a novel series of inhibitors of HCV NS5B, through the use of structure-based design applied to a fragment-derived starting point. Issues of potency, pharmacokinetics, and early safety were addressed in order to provide a clinical candidate in fluoropyridone 19.
Pharma Research & Early Development, Hoffmann-La Roche Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
Ryan C
RC
Schoenfeld
David L
DL
Bourdet
Ken A
KA
Brameld
Elbert
E
Chin
Javier
J
de Vicente
Amy
A
Fung
Seth F
SF
Harris
Eun K
EK
Lee
Sophie
S
Le Pogam
Vincent
V
Leveque
Jim
J
Li
Alfred S-T
AS
Lui
Isabel
I
Najera
Sonal
S
Rajyaguru
Michael
M
Sangi
Sandra
S
Steiner
Francisco X
FX
Talamas
Joshua P
JP
Taygerly
Junping
J
Zhao
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D045744:Cell Line, Tumor; D004285:Dogs; D055808:Drug Discovery / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D006526:Hepatitis C / Q000517:prevention & control / Q000821:virology; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D058990:Molecular Targeted Therapy / Q000379:methods; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011728:Pyridones / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011728:Pyridones; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase