Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: use of cyclopentane and cyclopentene P2-motifs |
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Authors: | Bäck Marcus Johansson Per-Ola Wångsell Fredrik Thorstensson Fredrik Kvarnström Ingemar Ayesa Susana Wähling Horst Pelcman Mikael Jansson Katarina Lindström Stefan Wallberg Hans Classon Björn Rydergård Christina Vrang Lotta Hamelink Elizabeth Hallberg Anders Rosenquist Sa Samuelsson Bertil |
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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 Organic Pharmaceutical Chemistry, Uppsala University, BMC, Box 574, S-751 23 Uppsala, Sweden;4. Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden |
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Abstract: | Several highly potent novel HCV NS3 protease inhibitors have been developed from two inhibitor series containing either a P2 trisubstituted macrocyclic cyclopentane- or a P2 cyclopentene dicarboxylic acid moiety as surrogates for the widely used N-acyl-(4R)-hydroxyproline in the P2 position. These inhibitors were optimized for anti HCV activities through examination of different ring sizes in the macrocyclic systems and further by exploring the effect of P4 substituent removal on potency. The target molecules were synthesized from readily available starting materials, furnishing the inhibitor compounds in good overall yields. It was found that the 14-membered ring system was the most potent in these two series and that the corresponding 13-, 15-, and 16-membered macrocyclic rings delivered less potent inhibitors. Moreover, the corresponding P1 acylsulfonamides had superior potencies over the corresponding P1 carboxylic acids. It is noteworthy that it has been possible to develop highly potent HCV protease inhibitors that altogether lack the P4 substituent. Thus the most potent inhibitor described in this work, inhibitor 20, displays a K(i) value of 0.41 nM and an EC(50) value of 9 nM in the subgenomic HCV replicon cell model on genotype 1b. To the best of our knowledge this is the first example described in the literature of a HCV protease inhibitor displaying high potency in the replicon assay and lacking the P4 substituent, a finding which should facilitate the development of orally active small molecule inhibitors against the HCV protease. |
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