62790-50-5Relevant articles and documents
Identification of DK419, a potent inhibitor of Wnt/β-catenin signaling and colorectal cancer growth
Wang, Jiangbo,Mook, Robert A.,Ren, Xiu-rong,Zhang, Qingfu,Jing, Genevieve,Lu, Min,Spasojevic, Ivan,Lyerly, H. Kim,Hsu, David,Chen, Wei
, p. 5435 - 5442 (2018)
The Wnt signaling pathway is critical for normal tissue development and is an underlying mechanism of disease when dysregulated. Previously, we reported that the drug Niclosamide inhibits Wnt/β-catenin signaling by decreasing the cytosolic levels of Dishevelled and β-catenin, and inhibits the growth of colon cancers both in vitro and in vivo. Since the discovery of Niclosamide's anthelmintic activity, a growing body of literature indicates that Niclosamide is a multifunctional drug. In an effort to identify derivatives of Niclosamide with improved pharmacokinetic properties that maintain the multifunctional drug activity of Niclosamide for clinical evaluation, we designed DK419, a derivative containing a 1H-benzo[d]imidazole-4-carboxamide substructure, using the structure-activity relationships (SAR) of the Niclosamide salicylanilide chemotype. Similar to Niclosamide, we found DK419 inhibited Wnt/β-catenin signaling, altered cellular oxygen consumption rate and induced production of pAMPK. Moreover, we found DK419 inhibited the growth of CRC tumor cells in vitro, had good plasma exposure when dosed orally, and inhibited the growth of patient derived CRC240 tumor explants in mice dosed orally. DK419, a derivative of Niclosamide with multifunctional activity and improved pharmacokinetic properties, is a promising agent to treat colorectal cancer, Wnt-related diseases and other diseases in which Niclosamide has demonstrated functional activity.
NICLOSAMIDE ANALOGUES AND THERAPEUTIC USE THEREOF
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Paragraph 00157, (2020/02/23)
Described are niclosamide analogue compounds, pharmaceutical compositions thereof, and method of using the compounds and compositions for treating a disease associated with dysregulation of the Wnt/Frizzled signaling pathway, such as cancer, fatty liver, antibiotic resistance, and viral infection. The disclosed compounds and compositions may also he used for modulating mitochondrial function and for treating certain non-cancer diseases and/or diorders, such as diabetes, fibrotic disease, primary sclerosing cholangitis.
CHEMICAL MODULATORS OF IMMUNE CHECKPOINTS AND THERAPEUTIC USE
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Paragraph 0242, (2017/07/29)
Compounds and pharmaceutical compositions that down-regulate immune checkpoints such as PD-1, PD-L1 and CTLA-4 are provided. Also provided are methods of treating a disease by down-regulating immune checkpoints such as PD-1, PD-L1 and CTLA-4. The methods
Optimization of potent, selective, and orally bioavailable pyrrolodinopyrimidine-containing inhibitors of heat shock protein 90. Identification of development candidate 2-amino-4-{4-chloro-2-[2-(4-fluoro-1h- pyrazol-1-yl)ethoxy]-6-methylphenyl}-n-(2,2-difluoropropyl)-5, 7-dihydro-6h-pyrrolo[3,4-d]pyrimidine-6-carboxamide
Zehnder, Luke,Bennett, Michael,Meng, Jerry,Huang, Buwen,Ninkovic, Sacha,Wang, Fen,Braganza, John,Tatlock, John,Jewell, Tanya,Zhou, Joe Zhongxiang,Burke, Ben,Wang, Jeff,Maegley, Karen,Mehta, Pramod P.,Yin, Min-Jean,Gajiwala, Ketan S.,Hickey, Michael J.,Yamazaki, Shinji,Smith, Evan,Kang, Ping,Sistla, Anand,Dovalsantos, Elena,Gehring, Michael R.,Kania, Robert,Wythes, Martin,Kung, Pei-Pei
supporting information; experimental part, p. 3368 - 3385 (2011/06/27)
Figure Presented. A novel class of heat shock protein 90 (Hsp90) inhibitors was discovered by high-throughput screening and was subsequently optimized using a combination of structure-based design, parallel synthesis, and the application of medicinal chemistry principles. Through this process, the biochemical and cell-based potency of the original HTS lead were substantially improved along with the corresponding metabolic stability properties. These efforts culminated with the identification of a development candidate (compound 42) which displayed desired PK/PD relationships, significant efficacy in a melanoma A2058 xenograft tumor model, and attractive DMPK profiles.
Broad spectrum chemistry as practised by Novartis process research
Mickel, Stuart J.,Fischer, Reto,Marterer, Wolfgang
, p. 640 - 648 (2007/10/03)
Three actual examples from the current product palette within Novartis Process Research will demonstrate the some of the variety and challenges encountered in modern chemical development.
The nitration of 8-methylquinoxalines in mixed acid
Marterer, Wolfgang,Prikoszovich, Walter,Wiss, Jacques,Prashad, Mahavir
, p. 318 - 323 (2013/09/06)
8-Methylquinoxalines are nitrated surprisingly efficiently at C-5 following a simple nitration protocol with mixed acid at 40-50°C. The implications of halogen functionalisation at C-6 and modification of the mixed acid conditions on the relative rates of conversion and process safety are discussed. Competing side reactions for 6-halo-8-methylquinoxalines involve hydrolysis at C-6 and halogenation at C-7 or C-5.
Research in 7-aminoindazole series: Synthesis of new halo-7H-4-methylpyrazolo[1,5,4-ef][1,5]benzodiazepin-6-ones and 5H-9-halo-6-methylpyrazolo[1,5,4-ef][1,5]benzodiazepin-4-ones
Rakib,Benchidmi,Essassi,El Bouadili,Ibn Mansour,Bellan,Lopez,Lamande
, p. 339 - 345 (2007/10/03)
A new class of 7-aminohaloindazoles has been synthesized. Reactivity of the amino groups of these bicyclic systems has been investigated. The halogenated pyrazolo-1,5-benzodiazepinones have been synthesized by the condensation of 7-aminoindazoles with ethyl acetoacetate.
Practical and efficient chlorination of deactivated anilines and anilides with NCS in 2-propanol
Zanka, Atsuhiko,Kubota, Ariyoshi
, p. 1984 - 1986 (2007/10/03)
Deactivated anilines and anilides were efficiently monochlorinated with NCS in 2-propanol. The described method was applicable to a large scale synthesis.
Oxidative Cyclizations. VII. Cyclization of 2-Substituted Anilines with Alkaline Hypohalite
Dyall, Leonard K.
, p. 2013 - 2026 (2007/10/02)
The Green-Rowe oxidation of 2-nitroanilines with alkaline hypohlorite, to yield benzofuroxans, is demonstrated by studies of the visible spectra of transient intermediates to proceed through N-chlorination and a singlet nitrene.Two variations on the route to the nitrene are possible.The cyclization step is represented as an internal capture of the nitrene by the ortho substituent, and on this basis the Green-Rowe oxidative cyclization is now extended to anilines whose ortho substituent is benzoyl or phenylazo.It is not however successful for ortho phenyl.Azo compounds were observed as byproducts in some of these reactions, and are shown to arise via N,N-dichloroanilines.