Discovery of Ruzasvir (MK-8408): A Potent, Pan-Genotype HCV NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Polymorphisms.
We describe the research that led to the discovery of compound 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a "flat" GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core while maintaining the imidazole-proline-valine Moc motifs of our previous NS5A inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection.
Ling
0000-0003-3302-8184
L
Tong
Wensheng
0000-0001-5978-9454
W
Yu
Lei
L
Chen
Oleg
O
Selyutin
Michael P
MP
Dwyer
Anilkumar G
AG
Nair
Robert
R
Mazzola
Jae-Hun
JH
Kim
Deyou
D
Sha
Jingjun
J
Yin
Rebecca T
RT
Ruck
Ian W
IW
Davies
Department of Medicinal Chemistry, WuXi AppTec , Shanghai, 200131, China.
Bin
B
Hu
Department of Medicinal Chemistry, WuXi AppTec , Shanghai, 200131, China.
Bin
B
Zhong
Department of Medicinal Chemistry, WuXi AppTec , Shanghai, 200131, China.
Jinglai
J
Hao
Department of Medicinal Chemistry, WuXi AppTec , Shanghai, 200131, China.
Tao
T
Ji
Department of Medicinal Chemistry, WuXi AppTec , Shanghai, 200131, China.
Shuai
S
Zan
Rong
R
Liu
Sony
S
Agrawal
Ellen
E
Xia
Stephanie
S
Curry
Patricia
P
McMonagle
Karin
K
Bystol
Frederick
F
Lahser
Donna
D
Carr
Laura
L
Rokosz
Paul
P
Ingravallo
Shiying
S
Chen
Kung-I
KI
Feng
Mark
M
Cartwright
Ernest
E
Asante-Appiah
Joseph A
JA
Kozlowski
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D004285:Dogs; D000882:Haplorhini; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D011110:Polymorphism, Genetic; D011759:Pyrrolidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D011759:Pyrrolidines; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C000621654:ruzasvir