- Design, synthesis, and evaluation of novel pyridone derivatives as potent BRD4 inhibitors for the potential treatment of prostate cancer
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Since androgen receptor (AR) can bind to BRD4 protein and this binding can be blocked by BRD4 inhibitors, targeting BRD4 has emerged as a promising approach for the treatment of prostate cancer (PC). Herein, we designed and synthesized a series of 5-(1-benzyl-1H-indazol-6-yl)-4-ethoxy-1-methylpyridin-2(1H)-one derivatives as novel BRD4 inhibitors for prostate cancer. Among them, compound 13 displayed the most robust BRD4 inhibitory activity with an IC50 value of 18 nM. Furthermore, 13 showed potent anti-proliferative activity against enzalutamide-resistant 22RV1 cells. The mechanism of action studies demonstrated that 13 induced cell apoptosis by regulating Bcl-2/Bax proteins and activating caspase-3 signaling pathway. In addition, the c-Myc level was significantly reduced in 22RV1 cells on the western blot assay. These findings collectively suggested that compound 13 might find potential use for the treatment of prostate cancer.
- Jiang, Wenhua,Wang, Xiaohui,Shu, Chengxia,Hou, Qiangqiang,Yang, Kexin,Wu, Xiaoxing
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supporting information
(2022/01/08)
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- SUBSTITUTED 5,6-DIPHENYL-3(2H)-PYRIDAZINONES FOR USE AS FUNGICIDES
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Disclosed are compounds of Formula (1) including all geometric and stereoisomers, N-oxides, and salts thereof, wherein W, R1, R2, R3, R4, R5 m, n and p are as defined in the disclosure. Also disclosed
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Page/Page column 37
(2021/08/20)
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- Nitrogen-substituted six-membered aromatic heterocyclic ketone compound as well as pharmaceutical composition, preparation method and application thereof
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The invention relates to a nitrogen-substituted six-membered aromatic heterocyclic ketone compound as well as a pharmaceutical composition, a preparation method and an application thereof. The invention particularly discloses nitrogen-substituted six-membered aromatic heterocyclic ketones shown as a general formula I, or pharmaceutically acceptable salts, prodrugs, isomers, racemates, precursors or solvates of the nitrogen-substituted six-membered aromatic heterocyclic ketones. The six-membered nitrogen-containing aromatic heterocyclic ketone compound disclosed by the invention is an efficientand high-selectivity BRD4 inhibitor; the compound has a good treatment effect on arthritis, autoimmune diseases or breast cancer, brain cancer, cervical cancer, colorectal cancer, gastrointestinal cancer, esophageal cancer, liver cancer, lung cancer, pancreatic cancer, endometrial cancer, nasopharyngeal carcinoma, ovarian cancer, prostate cancer, hematogenic system tumor and other diseases. The invention also discloses a preparation method and an application of the compound as shown in the general formula I.
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Paragraph 0148; 0149; 0150-0152
(2020/07/21)
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- Fragment-Based, Structure-Enabled Discovery of Novel Pyridones and Pyridone Macrocycles as Potent Bromodomain and Extra-Terminal Domain (BET) Family Bromodomain Inhibitors
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Members of the BET family of bromodomain containing proteins have been identified as potential targets for blocking proliferation in a variety of cancer cell lines. A two-dimensional NMR fragment screen for binders to the bromodomains of BRD4 identified a
- Wang, Le,Pratt, John K.,Soltwedel, Todd,Sheppard, George S.,Fidanze, Steven D.,Liu, Dachun,Hasvold, Lisa A.,Mantei, Robert A.,Holms, James H.,McClellan, William J.,Wendt, Michael D.,Wada, Carol,Frey, Robin,Hansen, T. Matthew,Hubbard, Robert,Park, Chang H.,Li, Leiming,Magoc, Terrance J.,Albert, Daniel H.,Lin, Xiaoyu,Warder, Scott E.,Kovar, Peter,Huang, Xiaoli,Wilcox, Denise,Wang, Rongqi,Rajaraman, Ganesh,Petros, Andrew M.,Hutchins, Charles W.,Panchal, Sanjay C.,Sun, Chaohong,Elmore, Steven W.,Shen, Yu,Kati, Warren M.,McDaniel, Keith F.
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p. 3828 - 3850
(2017/05/19)
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- PHTHALAZINE DERIVATIVES OF FORMULA (I) AS PCAF AND GCN5 INHIBITORS FOR USE IN THE TREATMENT OF CANCER
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The present invention relates to methods for treating PCAF and GCN5 mediated disorders using a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein ring A, R1, R3, R4, R5, and each Re have any of the values defined in the specification. Also included are novel compounds of Formula (I) and salts thereof, as well as pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
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Page/Page column 61-62
(2016/03/19)
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- PYRIDINONE AND PYRIDAZINONE DERIVATIVES
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Compounds of formula (I) wherein A1, A2, A3, A4, J, L, G, and R1 have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions, including inflammatory diseases, diabetes, obesity, cancer, and AIDS are disclosed. Pharmaceutical compositions comprising one or more compounds of formula (I) also are disclosed.
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Page/Page column 64; 71
(2014/01/08)
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- Pyridinone and Pyridazinone Derivatives
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The present invention provides for compounds of formula (I) wherein A1, A2, A3, A4, J, and X3 have any of the values defined therefor in the specification, and pharmaceutically acceptable salts thereo
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Paragraph 0750
(2014/01/08)
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- Studies on Syntheses and Reactions of Methoxypyridazines. II. Methoxylation of 3,4,6-Trichloropyridazine
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Methoxylation of 3,4,6-trichloropyridazine (1) with sodium methoxide was investigated in detail.Dimethoxylation of 1 afforded 6-chloro-3,4-dimethoxypyridazine (5) and a molecular complex (M) which is composed of 5 and 3-chloro-4,6-dimethoxypyridazine (6) in a ratio of 1:1.The nature of the complex (M) was examined by thermal and X-ray analyses.The molecular complex (M) was also obtained by monomethoxylation of 3,6-dichloro-4-methoxypyridazine (3) with sodium methoxide. Keywords --- 3,4,6-trichloropyridazine; methoxylation; pyridazinone; dimethoxymonochloropyridazine; trimethoxypyridazine; molecular complex; thermal analysis; X-ray analysis
- Nagashima, Hiromu,Ukai, Kiyoshi,Oda, Hirohisa,Masaki, Yukio,Kaji, Kenji
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p. 350 - 356
(2007/10/02)
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- Cephalosporins
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Cephalosporins represented by the formula X-S-Y wherein X is a deacetoxycephalosporinyl group and Y is a 6-membered heterocyclic group containing 1-3 nitrogens at least one of which is substituted and at least one of which is adjacent to a carbonyl group, said heterocyclic group containing one or more ring substituents and being characterized by being non-aromatic and not enolizable to an aromatic form.
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