1369487-49-9Relevant academic research and scientific papers
Synthesis and biological activity of conformationally restricted indole-based inhibitors of neurotropic alphavirus replication: Generation of a three-dimensional pharmacophore
Barraza, Scott J.,Sindac, Janice A.,Dobry, Craig J.,Delekta, Philip C.,Lee, Pil H.,Miller, David J.,Larsen, Scott D.
, (2021/06/18)
We have previously reported the development of indole-based CNS-active antivirals for the treatment of neurotropic alphavirus infection, but further optimization is impeded by a lack of knowledge of the molecular target and binding site. Herein we describe the design, synthesis and evaluation of a series of conformationally restricted analogues with the dual objectives of improving potency/selectivity and identifying the most bioactive conformation. Although this campaign was only modestly successful at improving potency, the sharply defined SAR of the rigid analogs enabled the definition of a three-dimensional pharmacophore, which we believe will be of value in further analog design and virtual screening for alternative antiviral leads.
Novel inhibitors of neurotropic alphavirus replication that improve host survival in a mouse model of acute viral encephalitis
Sindac, Janice A.,Yestrepsky, Bryan D.,Barraza, Scott J.,Bolduc, Kyle L.,Blakely, Pennelope K.,Keep, Richard F.,Irani, David N.,Miller, David J.,Larsen, Scott D.
, p. 3535 - 3545 (2012/06/17)
Arboviral encephalitis is a potentially devastating human disease with no approved therapies that target virus replication. We previously discovered a novel class of thieno[3,2-b]pyrrole-based inhibitors active against neurotropic alphaviruses such as western equine encephalitis virus (WEEV) in cultured cells. In this report, we describe initial development of these novel antiviral compounds, including bioisosteric replacement of the 4H-thieno[3,2-b]pyrrole core with indole to improve metabolic stability and the introduction of chirality to assess target enantioselectivity. Selected modifications enhanced antiviral activity while maintaining low cytotoxicity, increased stability to microsomal metabolism, and also revealed striking enantiospecific activity in cultured cells. Furthermore, we demonstrate improved outcomes (both symptoms and survival) following treatment with indole analogue 9h (CCG-203926) in an in vivo mouse model of alphaviral encephalitis that closely correlate with the enantiospecific in vitro antiviral activity. These results represent a substantial advancement in the early preclinical development of a promising class of novel antiviral drugs against virulent neurotropic alphaviruses.
ARBOVIRUS INHIBITORS AND USES THEREOF
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, (2012/10/08)
The present invention relates to chemical compounds, methods for their discovery, and their therapeutic use. In particular, the present invention provides compounds as inhibitors of arboviruses.
