Evaluation of the anti-hepatitis C virus effect of novel potent, selective, and orally bioavailable JNK and VEGFR kinase inhibitors.
Screening of a focused library of TGF beta kinase inhibitors in the cellular HCV replicon model with luciferase read out yielded a number of low micromolar HCV inhibitors. Medicinal chemistry driven optimization resulted in the discovery of 4-[2-(5-bromo-2-fluoro-phenyl)pteridin-4-ylamino]-N-[3-(2- oxopyrrolidin-1-yl)propyl]nicotinamide 36 with a replicon EC(50) of 64nM, associated with a selective kinase inhibitory profile for human JNK kinases 2 and 3 as well as VEGFR-1, 2, and 3 kinases. Moreover, 36 showed an advantageous PK profile in mice. Experiments performed using different replicon constructs suggest that this series of kinase inhibitors might mediate their effect through the HCV non-structural protein 5A (NS5A).
Raboisson
Pierre
P
Tibotec BVBA, Gen. De Wittelaan L11 B3, B-2800 Mechelen, Belgium. praboiss@tibbe.jnj.com
Lenz
Oliver
O
Lin
Tse-I
TI
Surleraux
Dominique
D
Chakravarty
Sarvajit
S
Scholliers
Annick
A
Vermeiren
Katrien
K
Delouvroy
Frederic
F
Verbinnen
Thierry
T
Simmen
Kenneth
K
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D019540:Area Under Curve; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005069:Evaluation Studies as Topic; D016174:Hepacivirus / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008956:Models, Chemical; D008968:Molecular Conformation; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors*; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000494:pharmacology*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D048670:MAP Kinase Kinase 4; D040281:Vascular Endothelial Growth Factor Receptor-1; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase