作为丙型肝炎病毒蛋白酶抑制剂的带有四肽基α-酮酰胺的双环脯氨酸P2的P4和P1'优化
P4 and P1' optimization of bicycloproline P2 bearing tetrapeptidyl alpha-ketoamides as HCV protease inhibitors.
作者信息
Yip Yvonne, Victor Frantz, Lamar Jason, Johnson Robert, Wang Q May, Glass John I, Yumibe Nathan, Wakulchik Mark, Munroe John, Chen Shu-Hui
机构信息
Lilly Research Laboratory, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
出版信息
Bioorg Med Chem Lett. 2004 Oct 4;14(19):5007-11. doi: 10.1016/j.bmcl.2004.07.007.
With the aim of improving HCV protease inhibitors reported in our previous manuscripts, we synthesized and evaluated a series of 1a-based tetrapeptidyl alpha-ketoamides with additional P4 modification. The promising analog discovered through this SAR, 5a, was further derivatized at P1' or P1 position. As a result of these efforts, we found that replacement of the P4 valine as seen in 1a with cyclohexylglycine (Chg) resulted in the discovery of 5a, 5c, and 5e endowed with improved cellular activity in comparison to 1a.
为了改进我们之前稿件中报道的丙型肝炎病毒（HCV）蛋白酶抑制剂，我们合成并评估了一系列基于1a的四肽基α-酮酰胺，并对P4进行了额外修饰。通过这种构效关系（SAR）发现的有前景的类似物5a，在P1'或P1位置进一步衍生化。经过这些努力，我们发现用环己基甘氨酸（Chg）取代1a中的P4缬氨酸，得到了5a、5c和5e，与1a相比，它们具有更高的细胞活性。
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