503000-87-1Relevant articles and documents
Structure-Guided Optimization of HIV Integrase Strand Transfer Inhibitors
Zhao, Xue Zhi,Smith, Steven J.,Maskell, Daniel P.,Métifiot, Mathieu,Pye, Valerie E.,Fesen, Katherine,Marchand, Christophe,Pommier, Yves,Cherepanov, Peter,Hughes, Stephen H.,Burke, Terrence R.
, p. 7315 - 7332 (2017)
Integrase mutations can reduce the effectiveness of the first-generation FDA-approved integrase strand transfer inhibitors (INSTIs), raltegravir (RAL) and elvitegravir (EVG). The second-generation agent, dolutegravir (DTG), has enjoyed considerable clinical success; however, resistance-causing mutations that diminish the efficacy of DTG have appeared. Our current findings support and extend the substrate envelope concept that broadly effective INSTIs can be designed by filling the envelope defined by the DNA substrates. Previously, we explored 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides as an INSTI scaffold, making a limited set of derivatives, and concluded that broadly effective INSTIs can be developed using this scaffold. Herein, we report an extended investigation of 6-substituents as well the first examples of 7-substituted analogues of this scaffold. While 7-substituents are not well-tolerated, we have identified novel substituents at the 6-position that are highly effective, with the best compound (6p) retaining better efficacy against a broad panel of known INSTI resistant mutants than any analogues we have previously described.
Design of Development Candidate eFT226, a First in Class Inhibitor of Eukaryotic Initiation Factor 4A RNA Helicase
Ernst, Justin T.,Thompson, Peggy A.,Nilewski, Christian,Sprengeler, Paul A.,Sperry, Samuel,Packard, Garrick,Michels, Theodore,Xiang, Alan,Tran, Chinh,Wegerski, Christopher J.,Eam, Boreth,Young, Nathan P.,Fish, Sarah,Chen, Joan,Howard, Haleigh,Staunton, Jocelyn,Molter, Jolene,Clarine, Jeff,Nevarez, Andres,Chiang, Gary G.,Appleman, Jim R.,Webster, Kevin R.,Reich, Siegfried H.
supporting information, p. 5879 - 5955 (2020/07/03)
Dysregulation of protein translation is a key driver for the pathogenesis of many cancers. Eukaryotic initiation factor 4A (eIF4A), an ATP-dependent DEAD-box RNA helicase, is a critical component of the eIF4F complex, which regulates cap-dependent protein synthesis. The flavagline class of natural products (i.e., rocaglamide A) has been shown to inhibit protein synthesis by stabilizing a translation-incompetent complex for select messenger RNAs (mRNAs) with eIF4A. Despite showing promising anticancer phenotypes, the development of flavagline derivatives as therapeutic agents has been hampered because of poor drug-like properties as well as synthetic complexity. A focused effort was undertaken utilizing a ligand-based design strategy to identify a chemotype with optimized physicochemical properties. Also, detailed mechanistic studies were undertaken to further elucidate mRNA sequence selectivity, key regulated target genes, and the associated antitumor phenotype. This work led to the design of eFT226 (Zotatifin), a compound with excellent physicochemical properties and significant antitumor activity that supports clinical development.
Halogenated allyl amine type SSAO/VAP-1 inhibitor and application thereof
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Paragraph 0315; 0319-0321, (2019/06/08)
The invention belongs to the technical field of medicine, and particularly relates to a halogenated allyl amine type compound shown as a formula I, medically acceptable salt, ester or stereo isomers thereof, wherein R1, R2, R3, R4, R5, R6, L1, Cy1, R7 and p are defined in description. The invention also relates to a medicine preparation containing the compounds, a medicine composition containing the compounds, and application of the compounds to prevention and/or treatment on diseases relevant to SSAO/VAP 1 protein or diseases caused by SSAO/VAP 1 protein mediating. The formula I is shown in the description.
