Tetracyclic indole inhibitors of hepatitis C virus NS5B-polymerase |
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| Authors: | Ian Stansfield Caterina Ercolani Angela Mackay Immacolata Conte Marco Pompei Uwe Koch Nadia Gennari Claudio Giuliano Michael Rowley Frank Narjes |
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| Affiliation: | 1. Department of Medicinal Chemistry, Istituto di Ricerche di Biologia Molecolare “P. Angeletti” S.p.A., Merck Research Laboratories Rome, 00040 Pomezia, Italy;2. Department of Computational Science, Istituto di Ricerche di Biologia Molecolare “P. Angeletti” S.p.A., Merck Research Laboratories Rome, 00040 Pomezia, Italy;3. Department of Pharmacology, Istituto di Ricerche di Biologia Molecolare “P. Angeletti” S.p.A., Merck Research Laboratories Rome, 00040 Pomezia, Italy;4. Department of Drug Metabolism Discovery and Development, Istituto di Ricerche di Biologia Molecolare “P. Angeletti” S.p.A., Merck Research Laboratories Rome, 00040 Pomezia, Italy |
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| Abstract: | 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. |
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