Synthesis of novel potent hepatitis C virus NS3 protease inhibitors: discovery of 4-hydroxy-cyclopent-2-ene-1,2-dicarboxylic acid as a N-acyl-L-hydroxyproline bioisostere.
Potent tetrapeptidic inhibitors of the HCV NS3 protease have been developed incorporating 4-hydroxy-cyclopent-2-ene-1,2-dicarboxylic acid as a new N-acyl-l-hydroxyproline mimic. The hydroxycyclopentene template was synthesized in eight steps from commercially available (syn)-tetrahydrophthalic anhydride. Three different amino acids were explored in the P1-position and in the P2-position the hydroxyl group of the cyclopentene template was substituted with 7-methoxy-2-phenyl-quinolin-4-ol. The P3/P4-positions were then optimized from a set of six amino acid derivatives. All inhibitors were evaluated in an in vitro assay using the full-length NS3 protease. Several potent inhibitors were identified, the most promising exhibiting a K(i) value of 1.1nM.
Thorstensson
Fredrik
F
Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden.
Wångsell
Fredrik
F
Kvarnström
Ingemar
I
Vrang
Lotta
L
Hamelink
Elizabeth
E
Jansson
Katarina
K
Hallberg
Anders
A
Rosenquist
Sa
S
Samuelsson
Bertil
B
D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000494:pharmacology*; D003998:Dicarboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D003517:Cyclopentanes; D003998:Dicarboxylic Acids; D007202:Indicators and Reagents; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C517810:4-hydroxy-cyclopent-2-ene-1,2-dicarboxylic acid; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases