PMID- 23544424
OWN - NLM
STAT- MEDLINE
DCOM- 20140515
LR  - 20140313
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 57
IP  - 5
DP  - 2014 Mar 13
TI  - Hepatitis C replication inhibitors that target the viral NS4B protein.
PG  - 2107-20
LID - 10.1021/jm400125h [doi]
AB  - We describe the preclinical development and in vivo efficacy of a novel chemical 
      series that inhibits hepatitis C virus replication via direct interaction with 
      the viral nonstructural protein 4B (NS4B). Significant potency improvements were 
      realized through isosteric modifications to our initial lead 1a. The temptation 
      to improve antiviral activity while compromising physicochemical properties was 
      tempered by the judicial use of ligand efficiency indices during lead 
      optimization. In this manner, compound 1a was transformed into (+)-28a which 
      possessed an improved antiviral profile with no increase in molecular weight and 
      only a modest elevation in lipophilicity. Additionally, we employed a chimeric 
      "humanized" mouse model of HCV infection to demonstrate for the first time that a 
      small molecule with high in vitro affinity for NS4B can inhibit viral replication 
      in vivo. This successful proof-of-concept study suggests that drugs targeting 
      NS4B may represent a viable treatment option for curing HCV infection.
FAU - Miller, John F
AU  - Miller JF
AD  - GlaxoSmithKline Research and Development , 5 Moore Drive, Research Triangle Park, 
      North Carolina 27709, United States.
FAU - Chong, Pek Y
AU  - Chong PY
FAU - Shotwell, J Brad
AU  - Shotwell JB
FAU - Catalano, John G
AU  - Catalano JG
FAU - Tai, Vincent W-F
AU  - Tai VW
FAU - Fang, Jing
AU  - Fang J
FAU - Banka, Anna L
AU  - Banka AL
FAU - Roberts, Christopher D
AU  - Roberts CD
FAU - Youngman, Michael
AU  - Youngman M
FAU - Zhang, Huichang
AU  - Zhang H
FAU - Xiong, Zhiping
AU  - Xiong Z
FAU - Mathis, Amanda
AU  - Mathis A
FAU - Pouliot, Jeffery J
AU  - Pouliot JJ
FAU - Hamatake, Robert K
AU  - Hamatake RK
FAU - Price, Daniel J
AU  - Price DJ
FAU - Seal, John W 3rd
AU  - Seal JW 3rd
FAU - Stroup, Lisa L
AU  - Stroup LL
FAU - Creech, Katrina L
AU  - Creech KL
FAU - Carballo, Luz H
AU  - Carballo LH
FAU - Todd, Dan
AU  - Todd D
FAU - Spaltenstein, Andrew
AU  - Spaltenstein A
FAU - Furst, Sylvia
AU  - Furst S
FAU - Hong, Zhi
AU  - Hong Z
FAU - Peat, Andrew J
AU  - Peat AJ
LA  - eng
PT  - Journal Article
DEP - 20130419
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Antiviral Agents)
RN  - 0 (NS4B protein, flavivirus)
RN  - 0 (Prodrugs)
RN  - 0 (Viral Nonstructural Proteins)
SB  - IM
MH  - Animals
MH  - Antiviral Agents/chemistry/pharmacokinetics/*pharmacology
MH  - Area Under Curve
MH  - Disease Models, Animal
MH  - Hepacivirus/*drug effects/physiology
MH  - Hepatitis C/virology
MH  - Mice
MH  - Prodrugs/chemistry/pharmacokinetics/pharmacology
MH  - Viral Nonstructural Proteins/*antagonists & inhibitors
MH  - Virus Replication/*drug effects
EDAT- 2013/04/03 06:00
MHDA- 2014/05/16 06:00
CRDT- 2013/04/03 06:00
PHST- 2013/04/03 06:00 [entrez]
PHST- 2013/04/03 06:00 [pubmed]
PHST- 2014/05/16 06:00 [medline]
AID - 10.1021/jm400125h [doi]
PST - ppublish
SO  - J Med Chem. 2014 Mar 13;57(5):2107-20. doi: 10.1021/jm400125h. Epub 2013 Apr 19.