Potent inhibitors of subgenomic hepatitis C virus RNA replication through optimization of indole-N-acetamide allosteric inhibitors of the viral NS5B polymerase.
Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. Compounds that block replication of subgenomic HCV RNA in liver cells are of interest because of their demonstrated antiviral effect in the clinic. In followup to our recent report that indole-N-acetamides (e.g., 1) are potent allosteric inhibitors of the HCV NS5B polymerase enzyme, we describe here their optimization as cell-based inhibitors. The crystal structure of 1 bound to NS5B was a guide in the design of a two-dimensional compound array that highlighted that formally zwitterionic inhibitors have strong intracellular potency and that pregnane X receptor (PXR) activation (an undesired off-target activity) is linked to a structural feature of the inhibitor. Optimized analogues devoid of PXR activation (e.g., 55, EC(50) = 127 nM) retain strong cell-based efficacy under high serum conditions and show acceptable pharmacokinetics parameters in rat and dog.
Harper
Steven
S
IRBM (Merck Research Laboratories, Rome), Pomezia, Italy. steven_harper@merck.com
Avolio
Salvatore
S
Pacini
Barbara
B
Di Filippo
Marcello
M
Altamura
Sergio
S
Tomei
Licia
L
Paonessa
Giacomo
G
Di Marco
Stefania
S
Carfi
Andrea
A
Giuliano
Claudio
C
Padron
Julio
J
Bonelli
Fabio
F
Migliaccio
Giovanni
G
De Francesco
Raffaele
R
Laufer
Ralph
R
Rowley
Michael
M
Narjes
Frank
F
D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000494:Allosteric Regulation; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D045744:Cell Line, Tumor; D004285:Dogs; D016679:Genome, Viral; D006207:Half-Life; D016174:Hepacivirus / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D000077297:Pregnane X Receptor; D012367:RNA, Viral / Q000187:drug effects*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D011987:Receptors, Steroid / Q000819:agonists; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000081:Acetamides; D000998:Antiviral Agents; D007211:Indoles; D000077297:Pregnane X Receptor; D012367:RNA, Viral; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase