- Design, synthesis and anticancer activities of novel dual poly(ADP-ribose) polymerase-1/histone deacetylase-1 inhibitors
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Currently, synergistic inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) and histone deacetylases (HDACs) has been a potential effective strategy for cancer treatment. Herein, by combining critical pharmacophores in approved drugs olaparib and chidamid
- Liao, Chenzhong,Tian, Yongbin,Xie, Zhouling
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- Phthalazine derivative, preparation method and applications thereof
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The invention discloses a phthalazine derivative, a preparation method and applications thereof, and belongs to the field of medicinal chemistry, wherein the phthalazine derivative prepared by the invention is a good PARP and HDAC double-target inhibitor.
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- Discovery of novel indoleamine 2,3-dioxygenase 1 (IDO1) and histone deacetylase 1 (HDAC1) dual inhibitors derived from the natural product saprorthoquinone
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The discovery of IDO1 and HDAC1 dual inhibitors may provide a novel strategy for cancer treatment by taking advantages of both immunotherapeutic and epigenetic drugs. In this paper, saprorthoquinone (1) and 13 of its analogues from Salvia prionitis Hance were investigated for their SAR against IDO1, the results demonstrated the ortho-quinone was a key pharmacophore. Then a series of IDO1 and HDAC dual inhibitors connected by appropriate linkers were designed, synthesized, and evaluated from the hit compound saprorthoquinone (1). Among them, compound 33d showed balanced activity against both IDO1 (IC50 = 0.73 μM) and HDAC1 (IC50 = 0.46 μM). Importantly, the structure of 33d suggested that an ortho-quinone pharmacophore and a N-(2- aminophenyl) amide pharmacophore were necessary for the IDO inhibition and HDAC inhibition respectively. Meanwhile, these two pharmacophore groups should be combined by a pentane linker. Moreover, the binding modes of 33d to the enzyme active site showed that the hydrogen bond with Leu234 of IDO1 appeared to confer increased potency to this class of inhibitors, which may explain the higher activity of 33d. This study provides a new strategy for future IDO1/HDAC dual inhibitors with synergistic antitumor activity started from lead compound 33d.
- Lin, Yang,Zhang, Heyanhao,Niu, Tong,Tang, Mei-Lin,Chang, Jun
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- Design, synthesis and biological evaluation of novel isoindolinone derivatives as potent histone deacetylase inhibitors
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Histone deacetylases (HDACs) as appealing targets for the treatment of many diseases has been studied extensively and its use in cancer care is the most important. Here, we developed a series of novel derivatives containing isoindolinone skeleton. Twelve compounds demonstrated nanomolar IC50 values against HDAC1, and the best compounds were 5a (65.6 nM), 5b (65.1 nM) and 13a (57.9 nM). In vitro, 5a and 5b also showed potent antiproliferative activities against several cancer cell lines, in particular 5b, which behaved better than approved drug chidamide. Morever, enzyme inhibition and western blot assay established 5b to be a selective inhibitor for HDAC1-3. Molecular docking was performed to rationalize the high potency of isoindolinones. Additionally, 5b had more appropriate drug metabolism in human liver microsome (HLM) compared with chidamide and moderate pharmacokinetics properties. These results indicated that 5b was worthy of further biological studies.
- Chen, Xin,Zhao, Shuang,Li, Hongmei,Wang, Xin,Geng, Aixin,Cui, Hao,Lu, Tao,Chen, Yadong,Zhu, Yong
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p. 110 - 122
(2019/02/25)
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- Histone histone deacetylase inhibitor and application thereof
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The invention provides a histone histone deacetylase inhibitor and application thereof. Specifically, the invention provides a compound of formula (I) as shown in the specification, and a pharmaceutically acceptable salt of the compound, and in the formula, the groups are defined as shown in the specification. The invention further provides a preparation method of the compound. The compound of formula (I), which is provided by the invention, can be adopted to treat a series of diseases mediated by histone histone deacetylases by inhibiting histone histone deacetylases (HDACs), particularly type-I histone histone deacetylases (subtypes such as HDAC1 and HDAC3), particularly including tumor diseases such as solid tumor and leukemia, neurodegenerative diseases, and the like.
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Paragraph 0164; 0166
(2018/04/26)
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- SUBSTITUTED PYRIMIDINE BMI-1 INHIBITORS
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Amine substituted pyrimidine compounds and forms thereof that inhibit the function and reduce the level of B -cell specific Moloney murine leukemia virus integration site 1 (Bmi-1) protein and methods for their use to inhibit Bmi-1 function and reduce the
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- NOVEL BENZODIAZEPINONES AS MODULATORS OF METABOTROPIC GLUTAMATE RECEPTOR FUNCTIONS AND NEUROLOGICAL USES THEREOF
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The present invention relates to novel benzodiazepinone compounds of Formulae (I) wherein R1, R2, R4, R6, R7, R8, R9, and R10 are as defined herein. The invention also
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Paragraph 0133; 0134; 0140
(2013/03/28)
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- Compositions Including 6-Aminohexanoic Acid Derivatives As HDAC Inhibitors
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This invention relates to compounds of Formula (I) wherein Cy1, L1, Y, R1, L2, and Ar2 are defined herein, for the treatment of cancers, inflammatory disorders, and neurological conditions.
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Page/Page column 42
(2012/04/23)
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- CDK INHIBITORS
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The present invention relates to CDK inhibitors and their use in the treatment of cell proliferative diseases such as cancer.
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Page/Page column 78
(2010/07/09)
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- 2,7,9-SUBSTITUTED PURINONE DERIVATIVES FOR IMMUNOSUPPRESSION
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The present invention provides novel purinone and related derivatives useful for the prevention and treatment of autoimmune diseases, inflammatory disease, mast cell mediated disease and transplant rejection. The compounds are of the general formula (I).
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- 2-Benzimidazolyl-9-(chroman-4-yl)-purinone derivatives as JAK3 inhibitors
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A novel class of Janus tyrosine kinase 3 (JAK3) inhibitors based on a 2-benzimidazoylpurinone core structure is described. Through substitution of the benzimidazoyl moiety and optimization of the N-9 substituent of the purinone, compound 24 was identified incorporating a chroman-based functional group. Compound 24 shows excellent kinase activity, good oral bioavailability and demonstrates efficacy in an acute mechanistic mouse model through inhibition of interleukin-2 (IL-2) induced interferon-γ (INF-γ) production.
- Cole, Andrew G.,Bohnstedt, Adolph C.,Paradkar, Vidyadhar,Kingsbury, Celia,Quintero, Jorge G.,Park, Haengsoon,Lu, Yingchun,You, Ming,Neagu, Irina,Diller, David J.,Letourneau, Jeffrey J.,Shao, Yuefei,James, Ray A.,Riviello, Christopher M.,Ho, Koc-Kan,Lin, Tsung H.,Wang, Bojing,Appell, Kenneth C.,Sills, Matthew,Quadros, Elizabeth,Kimble, Earl F.,Ohlmeyer, Michael H.J.,Webb, Maria L.
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scheme or table
p. 6788 - 6792
(2010/06/12)
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- BENZIMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AS FXR AGONISTS AND PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME
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The invention is concerned with novel benzimidazole derivatives of formula (I) wherein R1 to R8 are as defined in the description and in the claims, as well as physiologically acceptable salts and esters thereof. These compounds bind
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Page/Page column 118
(2008/06/13)
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- 7-Substituted Purine Derivatives for Immunosuppression
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The present invention provides novel purinone and related derivatives useful for the prevention and treatment of autoimmune diseases, inflammatory disease, mast cell mediated disease and transplant rejection. The compounds are of the general formula III:
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- 7-SUBSTITUTED PURINE DERIVATIVES FOR IMMUNOSUPPRESSION
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The present invention provides novel purinone and related derivatives useful for the prevention and treatment of autoimmune diseases, inflammatory disease, mast cell mediated disease and transplant rejection. The compounds are of the general formula (III).
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- 8-SUBSTITUTED 2-(BENZIMIDAZOLYL)PURINE DERIVATIVES FOR IMMUNOSUPPRESSION
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The present invention provides novel purines useful for the prevention and treatment of autoimmune diseases, inflammatory disease, mast cell mediated disease and transplant rejection. The compounds are of the general formula I:
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Page/Page column 15
(2008/06/13)
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- PURINE AND IMIDAZOPYRIDINE DERIVATIVES FOR IMMUNOSUPPRESSION
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The present invention provides novel purine and imidazopyridine derivatives useful for the prevention and treatment of autoimmune diseases, inflammatory disease, mast cell mediated disease and transplant rejection. The compounds are of the general formulas ( I ) and ( II ).
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Page/Page column 81-82
(2010/11/24)
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- Dihydro-benzo[b][1,4]diazepin-2-one derivatives
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This invention relates to dihydro-benzo[b][1,4]diazepin-2-one derivatives of the formula wherein R1, R2, X and Y are as defined in the specification and R3 is a six-membered aromatic heterocycle containing 1 to 3 nitrogen atoms or a pyridine-N-oxide as further defined in the specification. The invention further relates to medicaments containing these compounds, a process for their preparation as well as their use for preparation of medicaments for the treatment or prevention of acute and/or chronic neurological disorders.
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