Probing for improved selectivity with dipeptide-derived inhibitors of dipeptidyl peptidases 8 and 9: the impact of P1-variation
Probing for improved selectivity with dipeptide-derived inhibitors of dipeptidyl peptidases 8 and 9: the impact of P1-variation
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DOI：
10.1039/c5md00454c
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发表时间：
2016-01-01
期刊：
影响因子：
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通讯作者：
van der Veken, Pieter
中科院分区：
文献类型：
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作者：
Heirbaut, Leen;van Goethem, Sebastiaan;van der Veken, Pieter
选择的吡咯烷，2-氰基吡咯烷和杂芳族异吲哚啉类似物作为P1-残基的二肽衍生的抑制剂的DPP 8/9进行了评价。效价检测表明，使用选定的P1和P2片段集无法获得DPP 8或DPP 9特异性。尽管如此，纳摩尔DPP 8/9效力和相对于DPP IV和DPPII的显著选择性使得抑制剂4c和4 h成为未来抑制剂优化工作的合适“先导物”。
Selected pyrrolidines, 2-cyanopyrrolidines and heteroaromatic isoindoline analogues were evaluated as P1-residues in dipeptide-derived inhibitors of DPP8/9. Potency testing indicates that DPP8 or DPP9 specificity cannot be obtained with the selected set of P1- and P2-fragments. Nonetheless, the nanomolar DPP8/9 potencies and remarkable selectivities with respect to DPP IV and DPPII, makes inhibitors 4c and 4h suitable "leads" for future inhibitor optimization effort.