862175-16-4Relevant academic research and scientific papers
Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: Use of cyclopentane and cyclopentene P2-motifs
Baeck, Marcus,Johansson, Per-Ola,Wangsell, Fredrik,Thorstensson, Fredrik,Kvarnstroem, Ingemar,Ayesa, Susana,Waehling, Horst,Pelcman, Mikael,Jansson, Katarina,Lindstroem, Stefan,Wallberg, Hans,Classon, Bjoern,Rydergard, Christina,Vrang, Lotta,Hamelink, Elizabeth,Hallberg, Anders,Rosenquist, Asa,Samuelsson, Bertil
, p. 7184 - 7202 (2008/09/17)
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 Ki value of 0.41 nM and an EC50 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.
Potent inhibitors of the hepatitis C virus NS3 protease: Use of a novel P2 cyclopentane-derived template
Johansson, Per-Ola,Baeck, Marcus,Kvarnstroem, Ingemar,Jansson, Katarina,Vrang, Lotta,Hamelink, Elizabeth,Hallberg, Anders,Rosenquist, Asa,Samuelsson, Bertil
, p. 5136 - 5151 (2007/10/03)
The HCV NS3 protease is essential for replication of the hepatitis C virus (HCV) and therefore constitutes a promising new drug target for anti-HCV therapy. Several potent and promising HCV NS3 protease inhibitors, some of which display low nanomolar acti
HCV NS-3 SERINE PROTEASE INHIBITORS
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Page/Page column 130, (2008/06/13)
Peptidomimetic compounds are described which inhibit the NS3 protease of the hepatitis C virus (HCV). The compounds have the formula where the variable definitions are as provided in the specification. The compounds comprise a carbocyclic P2 unit in conjunction with a novel linkage to those portions of the inhibitor more distal to the nominal cleavage site of the native substrate, which linkage reverses the orientation of peptidic bonds on the distal side relative to those proximal to the cleavage site.
