Allosteric inhibitors of hepatitis C polymerase: discovery of potent and orally bioavailable carbon-linked dihydropyrones.
The discovery and optimization of a novel class of carbon-linked dihydropyrones as allosteric HCV NS5B polymerase inhibitors are presented. Replacement of the sulfur linker atom with carbon reduced compound acidity and greatly increased cell permeation. Further structure-activity relationship (SAR) studies led to the identification of compounds, exemplified by 23 and 24, with significantly improved antiviral activities in the cell-based replicon assay and favorable pharmacokinetic profiles.
Li
Hui
H
Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, California 92121, USA. hui.li@pfizer.com
Linton
Angelica
A
Tatlock
John
J
Gonzalez
Javier
J
Borchardt
Allen
A
Abreo
Mel
M
Jewell
Tanya
T
Patel
Leena
L
Drowns
Matthew
M
Ludlum
Sarah
S
Goble
Mike
M
Yang
Michele
M
Blazel
Julie
J
Rahavendran
Ravi
R
Skor
Heather
H
Shi
Stephanie
S
Lewis
Cristina
C
Fuhrman
Shella
S
D000284:Administration, Oral; D000494:Allosteric Regulation; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D006207:Half-Life; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D010539:Permeability; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D011753:Pyrones; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase