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 |
| |
Authors: | Thorstensson Fredrik Wångsell Fredrik Kvarnström Ingemar Vrang Lotta Hamelink Elizabeth Jansson Katarina Hallberg Anders Rosenquist Sa Samuelsson Bertil |
| |
Institution: | 1. Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden;2. Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden;3. Department of Medicinal Chemistry, BMC, Uppsala University, Box 574, S-751 23 Uppsala, Sweden;4. Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden |
| |
Abstract: | 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. |
| |
Keywords: | |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|