Novel HCV NS5B polymerase inhibitors derived from 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 5: Exploration of pyridazinones containing 6-amino-substituents.
The synthesis of 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones bearing 6-amino substituents as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC(50)<0.10 microM). In vitro DMPK data (microsome t(1/2), Caco-2 P(app)) for many of the compounds are also disclosed, and a crystal structure of a representative inhibitor complexed with the NS5B protein is discussed.
Dragovich
Peter S
PS
Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA. pdragovich@anadyspharma.com
Blazel
Julie K
JK
Ellis
David A
DA
Han
Qing
Q
Kamran
Ruhi
R
Kissinger
Charles R
CR
LeBrun
Laurie A
LA
Li
Lian-Sheng
LS
Murphy
Douglas E
DE
Noble
Michael
M
Patel
Rupal A
RA
Ruebsam
Frank
F
Sergeeva
Maria V
MV
Shah
Amit M
AM
Showalter
Richard E
RE
Tran
Chinh V
CV
Tsan
Mei
M
Webber
Stephen E
SE
Kirkovsky
Leo
L
Zhou
Yuefen
Y
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D018938:Caco-2 Cells; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000494:pharmacology; D012321:DNA-Directed RNA Polymerases / Q000737:chemistry; D015195:Drug Design; D005838:Genotype; D006801:Humans; D020128:Inhibitory Concentration 50; D008861:Microsomes / Q000378:metabolism; D008956:Models, Chemical; D008968:Molecular Conformation; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D003499:Cyclic S-Oxides; D012321:DNA-Directed RNA Polymerases; D011724:Pyridazines; D013829:Thiadiazines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase