| Literature DB >> 31537423 |
Michael B Plewe1, Landon R Whitby2, Shibani Naik1, Eric R Brown1, Nadezda V Sokolova1, Vidyasagar Reddy Gantla1, Joanne York3, Jack H Nunberg3, Lihong Zhang4, Birte Kalveram4, Alexander N Freiberg5, Dale L Boger6, Greg Henkel1, Ken McCormack7.
Abstract
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, R1 and R4 scanning libraries were assayed to identify potent substituents against Old World (Lassa) virus. In subsequent Phase II studies, R6 substituents and iterative R1, R4 and R6 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.Entities:
Keywords: Arenavirus; Entry inhibitor; Junin; Lassa; Machupo; Piperazinone
Year: 2019 PMID： 31537423 PMCID： PMC6803051 DOI： 10.1016/j.bmcl.2019.08.024
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823