Synthesis and biological characterization of B-ring amino analogues of potent benzothiadiazine hepatitis C virus polymerase inhibitors.
Benzothiadiazine inhibitors of the HCV NS5B RNA-dependent RNA polymerase are an important class of non-nucleoside inhibitors that have received considerable attention in the search for novel HCV therapeutics. Research in our laboratories has identified a novel series of tetracyclic benzothiadiazine inhibitors of HCV polymerase bearing a benzylamino substituent on the B-ring. Compounds in this series exhibit low-nanomolar activities in both genotypes 1a and 1b polymerase inhibition assays and subgenomic replicon assays. Optimization of pharmacokinetic properties in rat led to compound 30, which has good oral bioavailability (F = 56%) and a favorable tissue distribution drug profile, with high liver to plasma ratios. Compound 30 is a potent inhibitor in replicon assays, with EC(50) values of 10 and 6 nM against genotypes 1a and 1b, respectively.
Randolph
John T
JT
Global Pharmaceutical Research and Development, Abbott, 200 Abbott Park Road, Abbott Park, Illinois 60064-6217, USA. john.randolph@abbott.com
Flentge
Charles A
CA
Huang
Peggy P
PP
Hutchinson
Douglas K
DK
Klein
Larry L
LL
Lim
Hock B
HB
Mondal
Rubina
R
Reisch
Thomas
T
Montgomery
Debra A
DA
Jiang
Wen W
WW
Masse
Sherie V
SV
Hernandez
Lisa E
LE
Henry
Rodger F
RF
Liu
Yaya
Y
Koev
Gennadiy
G
Kati
Warren M
WM
Stewart
Kent D
KD
Beno
David W A
DW
Molla
Akhteruzzaman
A
Kempf
Dale J
DJ
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D001581:Benzothiadiazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D005838:Genotype; D016174:Hepacivirus / Q000201:enzymology* / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D000998:Antiviral Agents; D001426:Bacterial Proteins; D001581:Benzothiadiazines; D004791:Enzyme Inhibitors; D012324:RNA-Dependent RNA Polymerase