Department of Medicinal Chemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti S.p.A., Merck Research Laboratories Rome, 00040 Pomezia, Italy.
Bioorg Med Chem Lett. 2009 Feb 1;19(3):627-32. doi: 10.1016/j.bmcl.2008.12.068. Epub 2008 Dec 24.
We report the evolutionary path from an open-chain series to conformationally constrained tetracyclic indole inhibitors of HCV NS5B-polymerase, where the C2 aromatic is tethered to the indole nitrogen. SAR studies led to the discovery of zwitterionic compounds endowed with good intrinsic enzyme affinity and cell-based potency, as well as superior DMPK profiles to their acyclic counterparts, and ultimately to the identification of a pre-clinical candidate with an excellent predicted human pharmacokinetic profile.
我们报告了从开链系列到构象受限的四氢吲哚 HCV NS5B-聚合酶抑制剂的进化途径，其中 C2 芳基与吲哚氮相连。SAR 研究发现两性离子化合物具有良好的固有酶亲和力和基于细胞的效力，以及优于无环类似物的 DMPK 特征，并最终确定了具有优异预测人体药代动力学特征的临床前候选物。
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