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.
IRBM (Merck Research Laboratories, Rome), Pomezia, Italy. steven_harper@merck.com
Steven
S
Harper
Salvatore
S
Avolio
Barbara
B
Pacini
Marcello
M
Di Filippo
Sergio
S
Altamura
Licia
L
Tomei
Giacomo
G
Paonessa
Stefania
S
Di Marco
Andrea
A
Carfi
Claudio
C
Giuliano
Julio
J
Padron
Fabio
F
Bonelli
Giovanni
G
Migliaccio
Raffaele
R
De Francesco
Ralph
R
Laufer
Michael
M
Rowley
Frank
F
Narjes
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