- OXALAMIDE HETEROBYCYCLIC COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH STING ACTIVITY
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This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same.
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- Design, synthesis, and antiviral activity of entry inhibitors that target the CD4-binding site of HIV-1
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The CD4 binding site on HIV-1 gp120 has been validated as a drug target to prevent HIV-1 entry to cells. Previously, we identified two small molecule inhibitors consisting of a 2,2,6,6-tetramethylpiperidine ring linked by an oxalamide to a p-halide-substituted phenyl group, which target this site, specifically, a cavity termed "Phe43 cavity". Here we use synthetic chemistry, functional assessment, and structure-based analysis to explore variants of each region of these inhibitors for improved antiviral properties. Alterations of the phenyl group and of the oxalamide linker indicated that these regions were close to optimal in the original lead compounds. Design of a series of compounds, where the tetramethylpiperidine ring was replaced with new scaffolds, led to improved antiviral activity. These new scaffolds provide insight into the surface chemistry at the entrance of the cavity and offer additional opportunities by which to optimize further these potential-next- generation therapeutics and microbicides against HIV-1.
- Curreli, Francesca,Choudhury, Spreeha,Pyatkin, Ilya,Zagorodnikov, Victor P.,Bulay, Anna Khulianova,Altieri, Andrea,Kwon, Young Do,Kwong, Peter D.,Debnath, Asim K.
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p. 4764 - 4775
(2012/07/28)
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- CD4 mimics targeting the mechanism of HIV entry
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A structure-activity relationship study was conducted of several CD4 mimicking small molecules which block the interaction between HIV-1 gp120 and CD4. These CD4 mimics induce a conformational change in gp120, exposing its co-receptor-binding site. This induces a highly synergistic interaction in the use in combination with a co-receptor CXCR4 antagonist and reveals a pronounced effect on the dynamic supramolecular mechanism of HIV-1 entry.
- Yamada, Yuko,Ochiai, Chihiro,Yoshimura, Kazuhisa,Tanaka, Tomohiro,Ohashi, Nami,Narumi, Tetsuo,Nomura, Wataru,Harada, Shigeyoshi,Matsushita, Shuzo,Tamamura, Hirokazu
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experimental part
p. 354 - 358
(2010/04/05)
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