Pyridofuran substituted pyrimidine derivatives as HCV replication (replicase) inhibitors.
Introduction of nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzofuran inhibitor 2, resulted in the discovery of the more potent pyridofuran analogue 5. Subsequent introduction of small alkyl and alkoxy ligands into the pyridine ring resulted in further improvements in replicon potency. Replacement of the 4-chloro moiety on the pyrimidine core with a methyl group, and concomitant monoalkylation of the C-2 amino moiety resulted in the identification of several inhibitors with desirable characteristics. Inhibitor 41, from the monosubstituted pyridofuran and inhibitor 50 from the disubstituted series displayed excellent potency, selectivity (GAPDH/MTS CC(50)) and PK parameters in all species studied, while the selectivity in the thymidine incorporation assay (DNA·CC(50)) was low.
Merck Research Laboratories, Kenilworth, NJ 07033, USA. frank.bennett@merck.com
Frank
F
Bennett
Hollis S
HS
Kezar
Vinay
V
Girijavallabhan
Yuhua
Y
Huang
Regina
R
Huelgas
Randall
R
Rossman
Neng-Yang
NY
Shih
John J
JJ
Piwinski
Malcolm
M
MacCoss
Cecil D
CD
Kwong
Jeremy L
JL
Clark
Anita T
AT
Fowler
Feng
F
Geng
Abhijit
A
Roychowdhury
Robert C
RC
Reynolds
Joseph A
JA
Maddry
Subramaniam
S
Ananthan
John A
JA
Secrist
Cheng
C
Li
Robert
R
Chase
Stephanie
S
Curry
Hsueh-Cheng
HC
Huang
Xiao
X
Tong
F
F
George Njoroge
Ashok
A
Arasappan
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001572:Benzofurans / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006207:Half-Life; D016174:Hepacivirus / Q000201:enzymology*; D008099:Liver / Q000378:metabolism; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D001572:Benzofurans; D004791:Enzyme Inhibitors; D005663:Furans; D011741:Pyrimidine Nucleosides; D011743:Pyrimidines; D012324:RNA-Dependent RNA Polymerase; C030986:pyrimidine; C105430:benzofuran