SAR studies of 4-acyl-1,6-dialkylpiperazin-2-one arenavirus cell entry inhibitors
| Autor: | Eric Brown, Vidyasagar Reddy Gantla, Landon R. Whitby, Ken McCormack, Joanne York, Dale L. Boger, Plewe Michael Bruno, Birte Kalveram, Jack H. Nunberg, Greg Henkel, Alexander N. Freiberg, Nadezda V. Sokolova, Shibani Naik, Lihong Zhang |
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| Rok vydání: | 2019 |
| Předmět: |
Old World
viruses Clinical Biochemistry Pharmaceutical Science Microbial Sensitivity Tests 01 natural sciences Biochemistry Antiviral Agents Virus Piperazines Article Structure-Activity Relationship Viral Envelope Proteins Drug Discovery medicine Molecular Biology Arenavirus biology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry virus diseases biology.organism_classification Small molecule Virology In vitro 0104 chemical sciences Entry inhibitor 010404 medicinal & biomolecular chemistry Hemorrhagic Fevers Microsome Molecular Medicine medicine.drug |
| Zdroj: | Bioorg Med Chem Lett |
| ISSN: | 1464-3405 |
| Popis: | Old World (Africa) and New World (South America) arenaviruses are associated with human hemorrhagic fevers. Efforts to develop small molecule therapeutics have yielded several chemical series including the 4-acyl-1,6-dialkylpiperazin-2-ones. Herein, we describe an extensive exploration of this chemotype. In initial Phase I studies, R(1) and R(4) scanning libraries were assayed to identify potent substituents against Old World (Lassa) virus. In subsequent Phase II studies, R(6) substituents and iterative R(1), R(4) and R(6) substituent combinations were evaluated to obtain compounds with improved Lassa and New World (Machupo, Junin, and Tacaribe) arenavirus inhibitory activity, in vitro human liver microsome metabolic stability and aqueous solubility. |
| Databáze: | OpenAIRE |
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