- A Selective and Orally Bioavailable Quinoline-6-Carbonitrile-Based Inhibitor of CDK8/19 Mediator Kinase with Tumor-Enriched Pharmacokinetics
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Senexins are potent and selective quinazoline inhibitors of CDK8/19 Mediator kinases. To improve their potency and metabolic stability, quinoline-based derivatives were designed through a structure-guided strategy based on the simulated drug–target dockin
- Zhang, Li,Cheng, Chen,Li, Jing,Wang, Lili,Chumanevich, Alexander A.,Porter, Donald C.,Mindich, Aleksei,Gorbunova, Svetlana,Roninson, Igor B.,Chen, Mengqian,McInnes, Campbell
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supporting information
p. 3420 - 3433
(2022/02/16)
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- QUINOLINE-BASED COMPOUNDS AND METHODS OF INHIBITING CDK8/19
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Disclosed herein are quinoline-based compounds and method for inhibiting CDK8 or CDK19 for the intervention in diseases, disorders, and conditions. The quinoline-based composition comprise substituents at quinoline ring positions 4 and 6, wherein the substituent at position 4 is selected from a substituted or unsubstituted arylalkylamine or a substituted or unsubstituted arylhetrocyclylamine. Pharmaceutical compositions comprising the substituted qunioline compositions, methods of inhibiting CDK8 or CDK19, and methods of treating CDK8/19-associated diseases, disorders, or conditions are also disclosed.
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Paragraph 0108; 0110-0111; 0113
(2020/03/09)
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- Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel
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RIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor GSK583 and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compound was valuable in validating the biological pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog. Herein, we detail our efforts to improve both this off-target liability as well as the PK/PD profile of this series of inhibitors through modulation of lipophilicity and strengthening hinge binding ability. These efforts have led to inhibitor 7, which possesses high binding affinity for the ATP pocket of RIP2 (IC50 = 1 nM) and inhibition of downstream cytokine production in human whole blood (IC50 = 10 nM) with reduced hERG activity (14 μM).
- Haile, Pamela A.,Casillas, Linda N.,Bury, Michael J.,Mehlmann, John F.,Singhaus, Robert,Charnley, Adam K.,Hughes, Terry V.,Demartino, Michael P.,Wang, Gren Z.,Romano, Joseph J.,Dong, Xiaoyang,Plotnikov, Nikolay V.,Lakdawala, Ami S.,Convery, Maire A.,Votta, Bartholomew J.,Lipshutz, David B.,Desai, Biva M.,Swift, Barbara,Capriotti, Carol A.,Berger, Scott B.,Mahajan, Mukesh K.,Reilly, Michael A.,Rivera, Elizabeth J.,Sun, Helen H.,Nagilla, Rakesh,Lepage, Carol,Ouellette, Michael T.,Totoritis, Rachel D.,Donovan, Brian T.,Brown, Barry S.,Chaudhary, Khuram W.,Gough, Peter J.,Bertin, John,Marquis, Robert W.
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supporting information
p. 1039 - 1044
(2018/10/15)
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- The Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 Kinase
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RIP2 kinase is a central component of the innate immune system and enables downstream signaling following activation of the pattern recognition receptors NOD1 and NOD2, leading to the production of inflammatory cytokines. Recently, several inhibitors of R
- Haile, Pamela A.,Votta, Bartholomew J.,Marquis, Robert W.,Bury, Michael J.,Mehlmann, John F.,Singhaus, Robert,Charnley, Adam K.,Lakdawala, Ami S.,Convery, Máire A.,Lipshutz, David B.,Desai, Biva M.,Swift, Barbara,Capriotti, Carol A.,Berger, Scott B.,Mahajan, Mukesh K.,Reilly, Michael A.,Rivera, Elizabeth J.,Sun, Helen H.,Nagilla, Rakesh,Beal, Allison M.,Finger, Joshua N.,Cook, Michael N.,King, Bryan W.,Ouellette, Michael T.,Totoritis, Rachel D.,Pierdomenico, Maria,Negroni, Anna,Stronati, Laura,Cucchiara, Salvatore,Zió?kowski, Bart?omiej,Vossenk?mper, Anna,MacDonald, Thomas T.,Gough, Peter J.,Bertin, John,Casillas, Linda N.
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p. 4867 - 4880
(2016/06/13)
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- AMINO-QUINOLINES AS KINASE INHIBITORS
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Disclosed are quinoline compounds having the formula: wherein R1, R2 and A are as defined herein, and methods of making and using the same.
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Paragraph 0157; 0159
(2015/09/23)
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- QUINOLYL AMINES AS KINASE INHIBITORS
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Disclosed are compounds having the formula: wherein R1, R2, R3, R4 and R5 are as defined herein, and methods of making and using the same.
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Page/Page column 8; 10; 16
(2012/03/08)
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- Synthesis of novel halogenated 4(1H)-quinolones by thermolysis of arylaminomethylene-1,3-dioxane-4,6-diones
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A variety of novel 4(1H)-quinolone derivatives were prepared by thermolysis of aminomethylene Meldrum's acid derivatives. Georg Thieme Verlag Stuttgart.
- Rotzoll, Sven,Reinke, Helmut,Fischer, Christine,Langer, Peter
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experimental part
p. 69 - 78
(2009/06/17)
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- Controlled derivatization of polyhalogenated quinolines utilizing selective cross-coupling reactions
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Straightforward procedures for the derivatization of tri- and tetrahalogenated quinolines utilizing sequential selective Pd-catalyzed cross-coupling reactions are described. Taking advantage of intrinsic halide reactivity, substrate control, and appropria
- Brad Nolt,Zhao, Zhijian,Wolkenberg, Scott E.
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p. 3137 - 3141
(2008/09/20)
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- Compounds and Methods of Treatment
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A derivative, which is useful as a ret kinase inhibitor is described herein. The described invention also includes methods of using the same in the treatment of diseases mediated by inappropriate ret kinase activity.
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Page/Page column 24
(2008/12/08)
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- NOVEL QUINOLINE DERIVATIVES
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The invention relates to compounds represented by Formula (I): and to pharmaceutically acceptable salts or solvates of said compounds, wherein each of A, R3-8, X3, X5, m, and n are defined herein. The invention also relates to pharmaceutical compositions containing the compounds of Formula (I) and to methods of treating hyperproliferative disorders in a mammal by administering compounds of Formula (I).
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Page/Page column 64
(2008/06/13)
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