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- Lampa, Anna, et al.
(author)
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Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2–P1′ Region
- 2014
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In: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 5:3, s. 249-254
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Journal article (peer-reviewed)abstract
- Herein, novel hepatitis C virus NS3/4A protease inhibitors based on a P2 pyrimidinyloxyphenylglycine in combination with various regioisomers of an aryl acyl sulfonamide functionality in P1 are presented. The P1′ 4-(trifluoromethyl)phenyl side chain was shown to be particularly beneficial in terms of inhibitory potency. Several inhibitors with Ki-values in the nanomolar range were developed and included identification of promising P3-truncated inhibitors spanning from P2–P1′. Of several different P2 capping groups that were evaluated, a preference for the sterically congested Boc group was revealed. The inhibitors were found to retain inhibitory potencies for A156T, D168V, and R155K variants of the protease. Furthermore, in vitro pharmacokinetic profiling showed several beneficial effects on metabolic stability as well as on apparent intestinal permeability from both P3 truncation and the use of the P1′ 4-(trifluoromethyl)phenyl side chain.
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- Svahn Gustafsson, Sofia
(author)
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Characterization of HCV Protease Inhibitors : Inhibition and Interaction Studies with Applications for Drug Discovery
- 2013
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Doctoral thesis (other academic/artistic)abstract
- In this thesis, different approaches based on inhibition and interactions studies, have been used to characterize inhibitors of the non-structural protein 3 (NS3) from the hepatitis C virus (HCV). This involves identification of enzyme inhibitory effects and characterization of interaction mechanisms and kinetics, as well as effects on replication in a cell based system and serum protein binding. All this information contributes to HCV drug discovery.By using an inhibition assay it was possible to evaluate the effects of NS3 protease inhibitors, tested or used in the clinic, on NS3 variants, representing different model systems often used for drug discovery. This study illustrates the importance of accounting for differences in catalytic properties in comparative analyses, for making relevant interpretations of inhibition data. An SPR biosensor-based assay expanded the first study, and provided kinetic and mechanistic information, by direct interaction analyses of the inhibitors. It revealed significant differences between the different genotypes and model systems, and provided data that can be used to better understand the efficacy of inhibitors.Additionally, novel NS3 protease inhibitors were evaluated with respect to their potential to interfere with protease activity, their sensitivity to resistant mutants and effect on HCV replication. The most potent compounds were also characterized by their bioavailability, solubility and metabolic stability. This provides information for design of improved NS3 protease inhibitors, suggesting potential peptidomimetic structures for the backbone as well as for peptide substituents. These modification strategies allowed inhibitors to be truncated and less peptide-like, still with retained inhibitory effect.A new strategy for analysis of serum protein binding, of importance for drug distribution was also developed. By defining and using the concept of binding efficiency, serum protein interactions of moderate affinity, as described by rapid kinetics, were characterized. This strategy is also applicable for analysis of low affinity interactions.Taken together, all these studies provide knowledge and strategies for HCV drug discovery, and by using this information we might take a step closer to the final goal, which is to eradicate HCV.
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- Thorstensen, O, et al.
(author)
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MnDPDP enhancement in rabbit liver after intravenous bolus injection and slow infusion
- 1997
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In: Acta radiologica (Stockholm, Sweden : 1987). - : SAGE Publications. - 0284-1851 .- 1600-0455. ; 38:44 Pt 2, s. 717-723
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Journal article (peer-reviewed)abstract
- Purpose: To investigate the MR-enhancing effect of mangafodipir trisodium (MnDPDP, Teslascan) in the rabbit liver in relation to dose, mode of administration and imaging window. Material and Methods: MnDPDP was administered to 18 rabbits at a dose of 10 μmol/kg or 20 μmol/kg, as a bolus injection or infusion. MR imaging of the liver was performed at different time intervals. Results: Peak liver enhancement was typically observed 10–30 min after administration and the enhancement declined with a half-time of about 5 h. This pattern was observed in all sequences (SE 400/15, FLASH, and SE 132/10), with both doses and with both rates of administration. The peak enhancement was greater, though not significantly so after 20 μmol/kg than after 10 μmol/kg. A higher relative peak signal was observed with SE 132/10 than with FLASH or SE 400/15. Conclusion: A good liver imaging result was obtained after a dose of 10 μmol/kg, either bolus or infusion, 10–30 min post-contrast with heavily T1-weighted sequences.
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