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yaoguiyang木虫 (小有名气)
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[求助]
求助构效关系的翻译
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Modification of the P8 residue of the cyclosporin scaffold was instrumental to the development of some of the earliest cyclosporin−cyclophilin binding assays.73,121 Also, in their solid phase synthesis of 1 and related compounds, Ko and Wenger had reported that some P8-modified cyclosporin analogues were significantly less immunosuppressive than 1.71 Like the P3 residue, the P8 group is positioned on the edge of what is generally considered to be the calcineurin-binding (P4−P7) domain. The Scynexis group employed conditions similar to those introduced by Eberle and co-workers (Scheme 3) to explore the immunosuppressive activity of P8-modified cyclosporins. Their results suggested that cyclophilin A binding affinity, immunosuppressive activity, and antiviral activity could be modulated by appending basic groups in this position.122 Representative compound 17 (Figure 10) was found to have improved anti-HCV activity and reduced immunosuppressive action relative to 1. Cyclosporin A is very lipophilic and is widely distributed to tissue compartments in vivo. Plasma protein binding is reported to be approximately 95%, although determined values can vary dramatically.55 Analysis of the pharmacokinetic profile of cyclosporin A and other cyclophilin inhibitors is complicated by the high expression of cyclophilin A in blood cells, especially erythrocytes.56 This leads to a dose and exposure-dependent blood/plasma partitioning of cyclophilin inhibitors. For example, following oral administration, the exposure of the nonimmunosuppressive cyclophilin 8 in blood is not dose proportional while plasma exposure increases in a linear fashion.44 The immunosuppressive effect of cyclosporin A is associated with the unbound concentration in plasma,55 and it should be expected that the pharmacological efficacy of nonimmunosuppressive cyclophilin inhibitors would be proportional to free drug exposure in plasma. Therefore, relatively high total doses of cyclophilin inhibitors may be required to saturate binding of cyclosporin A in erythrocytes and provide free drug concentrations required for efficacy. |
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yaoguiyang
木虫 (小有名气)
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2楼2014-11-30 11:06:07
yaoguiyang
木虫 (小有名气)
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3楼2014-11-30 11:06:40
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