Discovery of potent macrocyclic HCV NS5A inhibitors.
HCV NS5A inhibitors have demonstrated impressive in vitro virologic profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed-dose combination (FDC) regimen for the treatment of HCV infection. Merck's effort in this area identified MK-4882 and MK-8325 as early development leads. Herein, we describe the discovery of potent macrocyclic NS5A inhibitors bearing the MK-8325 or MK-4882 core structure.
Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA. Electronic address: wensheng.yu@merck.com.
Wensheng
W
Yu
Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
Bancha
B
Vibulbhan
Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
Stuart B
SB
Rosenblum
Albany Molecular Research Inc., 26 Corporate Circle, Albany, NY 12203, USA.
Gregory S
GS
Martin
Albany Molecular Research Inc., 26 Corporate Circle, Albany, NY 12203, USA.
A Samuel
AS
Vellekoop
Albany Molecular Research Inc., 26 Corporate Circle, Albany, NY 12203, USA.
Christian L
CL
Holst
Department of Medicinal Chemistry, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA.
Craig A
CA
Coburn
Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
Michael
M
Wong
Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
Oleg
O
Selyutin
WuXi AppTec, 288 Fute Zhong Road, Shanghai 200131, China.
Tao
T
Ji
WuXi AppTec, 288 Fute Zhong Road, Shanghai 200131, China.
Bin
B
Zhong
WuXi AppTec, 288 Fute Zhong Road, Shanghai 200131, China.
Bin
B
Hu
Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
Lei
L
Chen
Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
Michael P
MP
Dwyer
Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
Yueheng
Y
Jiang
Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
Anilkumar G
AG
Nair
Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
Ling
L
Tong
Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
Qingbei
Q
Zeng
Department of In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Sony
S
Agrawal
Department of In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Donna
D
Carr
Department of In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Laura
L
Rokosz
Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Rong
R
Liu
Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Stephanie
S
Curry
Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Patricia
P
McMonagle
Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Paul
P
Ingravallo
Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Fred
F
Lahser
Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Ernest
E
Asante-Appiah
Department of Structural Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065 USA.
James
J
Fells
Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
Joseph A
JA
Kozlowski
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D047028:Macrocyclic Compounds; D017361:Viral Nonstructural Proteins; C000620694:MK-4882; C000620696:MK-8325; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
DAA; HCV NS5A inhibitor; HCV infection; MK-4882; MK-8325; Macrocycle