863605-02-1Relevant academic research and scientific papers
Discovery of a series of dihydroquinoxalin-2(1H)-ones as selective BET inhibitors from a dual PLK1-BRD4 inhibitor
Hu, Jianping,Wang, Yingqing,Li, Yanlian,Xu, Lin,Cao, Danyan,Song, ShanShan,Damaneh, Mohammadali Soleimani,Wang, Xin,Meng, Tao,Chen, Yue-Lei,Shen, Jingkang,Miao, Zehong,Xiong, Bing
, p. 176 - 195 (2017/06/07)
Recent years have seen much effort to discover new chemotypes of BRD4 inhibitors. Interestingly, some kinase inhibitors have been demonstrated to be potent bromodomain inhibitors, especially the PLK1 inhibitor BI-2536 and the JAK2 inhibitor TG101209, which can bind to BRD4 with IC50 values of 0.025 μM and 0.13 μM, respectively. Although the concept of dual inhibition is intriguing, selective BRD4 inhibitors are preferred as they may diminish off-target effects and provide more flexibility in anticancer drug combination therapy. Inspired by BI-2536, we designed and prepared a series of dihydroquinoxalin-2(1H)-one derivatives as selective bromodomain inhibitors. We found compound 54 had slightly higher activity than (+)-JQ1 in the fluorescence anisotropy assay and potent antiproliferative cellular activity in the MM.1S cell line. We have successfully solved the cocrystal structure of 52 in complex with BRD4-BD1, providing a solid structural basis for the binding mode of compounds of this series. Compound 54 exhibited high selectivity over most non-BET subfamily members and did not show bioactivity towards the PLK1 kinase at 10 or 1 μM. From in vivo studies, compound 54 demonstrated a good PK profile, and the results from in vivo pharmacological studies clearly showed the efficacy of 54 in the mouse MM.1S xenograft model.
BENZIMIDAZOLE DERIVATIVES AS ANTIVIRAL AGENTS
-
Page/Page column 212, (2013/02/28)
Provided are compounds of Formulas I, II, III, IV, V, and pharmaceutically acceptable salts thereof, their pharmaceutical compositions, their methods of preparation, and their use for treating viral infections mediated by a member of the Flaviviridae family of viruses such as hepatitis C virus (HCV).
Imidazolyl benzimidazoles and imidazo[4,5-b]pyridines as potent p38α MAP kinase inhibitors with excellent in vivo antiinflammatory properties
Mader, Mary,de Dios, Alfonso,Shih, Chuan,Bonjouklian, Rosanne,Li, Tiechao,White, Wesley,de Uralde, Beatriz Lopez,Sanchez-Martinez, Concepcion,del Prado, Miriam,Jaramillo, Carlos,de Diego, Eugenio,Martin Cabrejas, Luisa M.,Dominguez, Carmen,Montero, Carlos,Shepherd, Timothy,Dally, Robert,Toth, John E.,Chatterjee, Arindam,Pleite, Sehila,Blanco-Urgoiti, Jaime,Perez, Leticia,Barberis, Mario,Lorite, Maria Jose,Jambrina, Enrique,Nevill Jr., C. Richard,Lee, Paul A.,Schultz, Richard C.,Wolos, Jeffrey A.,Li, Li C.,Campbell, Robert M.,Anderson, Bryan D.
, p. 179 - 183 (2008/09/18)
Herein we report investigations into the p38α MAP kinase activity of trisubstituted imidazoles that led to the identification of compounds possessing highly potent in vivo activity. The SAR of a novel series of imidazopyridines is demonstrated as well, resulting in compounds possessing cellular potency and enhanced in vivo activity in the rat collagen-induced arthritis model of chronic inflammation.
GLUCOKINASE ACTIVATORS
-
Page/Page column 70-71, (2010/11/28)
Compounds, pharmaceutical compositions, kits and methods are provided for use with glucokinase that comprise a compound selected from the group consisting of: wherein the variables are as defined herein.
