Discovery and development of simeprevir (TMC435), a HCV NS3/4A protease inhibitor.
Hepatitis C virus is a blood-borne infection and the leading cause of chronic liver disease (including cirrhosis and cancer) and liver transplantation. Since the identification of HCV in 1989, there has been an extensive effort to identify and improve treatment options. An important milestone was reached in 2011 with the approval of the first-generation HCV NS3/4A protease inhibitors. However, new therapies are needed to improve cure rates, shorten treatment duration, and improve tolerability. Here we summarize the extensive medicinal chemistry effort to develop novel P2 cyclopentane macrocyclic inhibitors guided by HCV NS3 protease assays, the cellular replicon system, structure-based design, and a panel of DMPK assays. The selection of compound 29 (simeprevir, TMC435) as clinical candidate was based on its excellent biological, PK, and safety pharmacology profile. Compound 29 has recently been approved for treatment of chronic HCV infection in combination with pegylated interferon-α and ribavirin in Japan, Canada, and USA.
Medivir AB , P.O. Box 1086, SE-141 45 Huddinge, Sweden.
Åsa
Å
Rosenquist
Bertil
B
Samuelsson
Per-Ola
PO
Johansson
Maxwell D
MD
Cummings
Oliver
O
Lenz
Pierre
P
Raboisson
Kenny
K
Simmen
Sandrine
S
Vendeville
Herman
H
de Kock
Magnus
M
Nilsson
Andras
A
Horvath
Ronald
R
Kalmeijer
Guy
G
de la Rosa
Maria
M
Beumont-Mauviel
D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D055808:Drug Discovery; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry* / Q000494:pharmacology; D000069616:Simeprevir; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D006575:Heterocyclic Compounds, 3-Ring; D000069616:Simeprevir; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus