The discovery and optimization of naphthalene-linked P2-P4 Macrocycles as inhibitors of HCV NS3 protease
| Autor: | Dennis Hernandez, Ramkumar Rajamani, Rongti Li, Jacques Friborg, Fiona McPhee, Nicholas A. Meanwell, Kathy Mosure, Ying-Kai Wang, Jay O. Knipe, Fei Yu, Herbert E. Klei, Bowsher Michael S, Paul Michael Scola, Alan X. Wang, Sheldon Hiebert |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Proteases Macrocyclic Compounds Stereochemistry Clinical Biochemistry Drug Evaluation Preclinical Molecular Conformation Administration Oral Pharmaceutical Science Hepacivirus Naphthalenes Viral Nonstructural Proteins Antiviral Agents Biochemistry 03 medical and health sciences chemistry.chemical_compound Pharmacokinetics Drug Discovery Animals Potency Protease Inhibitors Molecular Biology Naphthalene chemistry.chemical_classification Organic Chemistry Heart Rats Bioavailability Sulfonamide 030104 developmental biology chemistry Hcv ns3 protease Lipophilicity Microsomes Liver Molecular Medicine Rabbits Half-Life |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 28:43-48 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2017.11.005 |
| Popis: | Naphthalene-linked P2-P4 macrocycles within a tri-peptide-based acyl sulfonamide chemotype have been synthesized and found to inhibit HCV NS3 proteases representing genotypes 1a and 1b with single digit nanomolar potency. The pharmacokinetic profile of compounds in this series was optimized through structural modifications along the macrocycle tether as well as the P1 subsite. Ultimately a compound with oral bioavailability of 100% in rat, and a long half-life in plasma was obtained. However, compounds in this macrocyclic series exhibited cardiac effects in an isolated rabbit heart model and for this reason further optimization efforts were discontinued. |
| Databáze: | OpenAIRE |
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