Finger loop inhibitors of the HCV NS5b polymerase. Part II. Optimization of tetracyclic indole-based macrocycle leading to the discovery of TMC647055.
Optimization of a novel series of macrocyclic indole-based inhibitors of the HCV NS5b polymerase targeting the finger loop domain led to the discovery of lead compounds exhibiting improved potency in cellular assays and superior pharmacokinetic profile. Further lead optimization performed on the most promising unsaturated-bridged subseries provided the clinical candidate 27-cyclohexyl-12,13,16,17-tetrahydro-22-methoxy-11,17-dimethyl-10,10-dioxide-2,19-methano-3,7:4,1-dimetheno-1H,11H-14,10,2,9,11,17-benzoxathiatetraazacyclo docosine-8,18(9H,15H)-dione, TMC647055 (compound 18a). This non-zwitterionic 17-membered ring macrocycle combines nanomolar cellular potency (EC(50) of 82 nM) with minimal associated cell toxicity (CC(50)>20 μM) and promising pharmacokinetic profiles in rats and dogs. TMC647055 is currently being evaluated in the clinic.
Janssen Infectious Diseases BVBA, 30 Turnhoutseweg, B-2340 Beerse, Belgium. svendev1@its.jnj.com
Sandrine
S
Vendeville
Tse-I
TI
Lin
Lili
L
Hu
Abdellah
A
Tahri
David
D
McGowan
Maxwell D
MD
Cummings
Katie
K
Amssoms
Maxime
M
Canard
Stefaan
S
Last
Iris
I
Van den Steen
Benoit
B
Devogelaere
Marie-Claude
MC
Rouan
Leen
L
Vijgen
Jan Martin
JM
Berke
Pascale
P
Dehertogh
Els
E
Fransen
Erna
E
Cleiren
Liesbet
L
van der Helm
Gregory
G
Fanning
Kristof
K
Van Emelen
Origène
O
Nyanguile
Kenny
K
Simmen
Pierre
P
Raboisson
D000494:Allosteric Regulation; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D016174:Hepacivirus / Q000201:enzymology*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D008099:Liver / Q000378:metabolism; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D007211:Indoles; D047028:Macrocyclic Compounds; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C575713:27-cyclohexyl-12,13,16,17-tetrahydro-22-methoxy-11,17-dimethyl-10,10-dioxide-2,19-methano-3,7:4,1-dimetheno-1H,11H-14,10,2,9,11,17-benzoxathiatetraazacyclo docosine-8,18(9H,15H)-dione; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase