- Discovery and Optimization of 2 H-1λ2-Pyridin-2-one Inhibitors of Mutant Isocitrate Dehydrogenase 1 for the Treatment of Cancer
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Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2H-1λ2-quinoline-2,5(6H)-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (+)-119 (NCATS-SM5637, NSC 791985). In an engineered mIDH1-U87-xenograft mouse model, after a single oral dose of 30 mg/kg, 16 h post dose, between 16 and 48 h, (+)-119 showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).
- Rohde, Jason M.,Karavadhi, Surendra,Pragani, Rajan,Liu, Li,Fang, Yuhong,Zhang, Weihe,McIver, Andrew,Zheng, Hongchao,Liu, Qingyang,Davis, Mindy I.,Urban, Daniel J.,Lee, Tobie D.,Cheff, Dorian M.,Hollingshead, Melinda,Henderson, Mark J.,Martinez, Natalia J.,Brimacombe, Kyle R.,Yasgar, Adam,Zhao, Wei,Klumpp-Thomas, Carleen,Michael, Sam,Covey, Joseph,Moore, William J.,Stott, Gordon M.,Li, Zhuyin,Simeonov, Anton,Jadhav, Ajit,Frye, Stephen,Hall, Matthew D.,Shen, Min,Wang, Xiaodong,Patnaik, Samarjit,Boxer, Matthew B.
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p. 4913 - 4946
(2021/05/07)
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- HETEROCYCLIC COMPOUNDS AND USES THEREOF
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Heterocyclic compounds as Weel inhibitors are provided. The compounds may find use as therapeutic agents for the treatment of diseases and may find particular use in oncology.
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Paragraph 0157
(2020/10/21)
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- MUTANT IDH1 INHIBITORS USEFUL FOR TREATING CANCER
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Compounds of Formula I and Formula II and the pharmaceutically acceptable salts thereof are disclosed The variables A, B, Y, Z, X1, X2, R1-4 and R13-18 are disclosed herein. The compounds are useful for treating cancer disorders, especially those involving mutant IDH1 enzymes. Pharmaceutical compositions containing compounds of Formula I or Formula II and methods of treatment comprising administering compounds of Formula I and Formula II are also disclosed.
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Paragraph 0157
(2016/07/27)
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- Facile synthesis of aryl-pyridyl, pyridazinyl, pyrazinyl, and triazinyl acetonitriles
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Dihalo pyridine, pyrazine, and pyridazine analogues were converted to the corresponding monohalo acetonitrile analogues through nucleophilic displacement of the halogen with the anion of tert-butyl cyanoacetate. The monohalo acetonitriles reacted under Su
- Farahat,Boykin
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p. 585 - 589
(2013/06/27)
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- INHIBITORS OF JANUS KINASES
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The instant invention provides for compounds that inhibit the four known mammalian JAK kinases (JAK1, JAK2, JAK3 and TYK2) and PDK1. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting the activity of JAK1, JAK2, JAK3, TYK2 and PDK1 by administering the compound to a patient in need of treatment for myeloproliferative disorders or cancer.
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Page/Page column 49
(2010/04/03)
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- BENZOFURAN DERIVATIVES USEFUL FOR TREATING HYPER-PROLIFERATIVE DISORDERS
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The invention relates to novel heterocycles of formula (I), processes for their preparation and their use for preparing medicaments for the treatment or prophylaxis of disorders, especially of hyperproliferative disorders.
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Page/Page column 87
(2008/06/13)
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- PYRIDINYL ACETONITRILES
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The present invention is related to pyridinyl acetonitriles as well as to pharmaceutical formulations containing such pyridinyl acetonitriles. Said pyridinyl acetonitriles are modulators of the protein kinase signalling pathways, particularly the one involving Glycogen Kinase Synthase 3 or JNK. The present invention is furthermore related to methods of preparing pyridinyl acetonitriles. X is a substituted or unsubstituted pyridinyl. G is an unsubstituted or substituted pyrimidinyl or triazinyl.
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Page/Page column 43-44
(2010/02/09)
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- Facile cyanomethylation of bromopyridines by nucleophilic substitution with lithioacetonitrile
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Substituted bromopyridines undergo facile nucleophilic substitution with lithioacetonitrile under mild conditions to afford the corresponding cyanomethylated products.
- Skerlj,Bogucki,Bridger
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p. 1488 - 1490
(2007/10/03)
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- Nitrile-Stabilized Carboanions. Nucleophilic Substitution Reactions on Bromopyridines
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A series of bis(2-heteroaryl)acetonitriles were synthesized, characterized, and transformed into the corresponding bis(2-heteroaryl)methanes, which can be readily oxidized with SeO2 in glacial acetic acid to the respective ketones.These disubstituted acetonitriles are ideal precursors to heterocalixarenes.The configuration in the solid state of meso-cyano compound 16 was ascertained by an X-ray crystal structure.
- Newkome, George R.,Joo, Young J.,Evans, David W.,Pappalardo, Sebastiano,Fronczek, Frank R.
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p. 786 - 790
(2007/10/02)
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