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
2007 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 15, no 2, 827-838 p.Article in journal (Refereed) Published
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 Ki value of 1.1 nM.
Place, publisher, year, edition, pages
2007. Vol. 15, no 2, 827-838 p.
Cyclopentanes/*chemical synthesis/*pharmacology, Dicarboxylic Acids/*chemical synthesis/*pharmacology, Indicators and Reagents, Kinetics, Magnetic Resonance Spectroscopy, Models; Molecular, Protease Inhibitors/*chemical synthesis/*pharmacology, Stereoisomerism, Structure-Activity Relationship, Viral Nonstructural Proteins/*antagonists & inhibitors
IdentifiersURN: urn:nbn:se:uu:diva-17096DOI: 10.1016/j.bmc.2006.10.044ISI: 000243315300021PubMedID: 17107807OAI: oai:DiVA.org:uu-17096DiVA: diva2:44867