- Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2-EED Interaction
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Disruption of EZH2-embryonic ectoderm development (EED) protein-protein interaction (PPI) is a new promising cancer therapeutic strategy. We have previously reported the discovery of astemizole, a small-molecule inhibitor targeting the EZH2-EED PPI. Herein, we report the cocrystal structure of EED in complex with astemizole at 2.15 ?. The structure elucidates the detailed binding mode of astemizole to EED and provides a structure-guided design for the discovery of a novel EZH2-EED interaction inhibitor, DC-PRC2in-01, with an affinityKdof 4.56 μM. DC-PRC2in-01 destabilizes the PRC2 complex, thereby leading to the degradation of PRC2 core proteins and the decrease of global H3K27me3 levels in cancer cells. The proliferation of PRC2-driven lymphomas cells is effectively inhibited, and the cell cycle is arrested in the G0/G1 phase. Together, these data demonstrate that DC-PRC2in-01 could be an effective chemical probe for investigating the PRC2-related physiology and pathology and providing a promising chemical scaffold for further development.
- Du, Daohai,Xu, Dandan,Zhu, Licheng,Stazi, Giulia,Zwergel, Clemens,Liu, Yanli,Luo, Zhongyuan,Li, Yuanqing,Zhang, Yuanyuan,Zhu, Kongkai,Ding, Yiluan,Liu, Jingqiu,Fan, Shijie,Zhao, Kaiyan,Zhang, Naixia,Kong, Xiangqian,Jiang, Hualiang,Chen, Kaixian,Zhao, Kehao,Valente, Sergio,Min, Jinrong,Duan, Wenhu,Luo, Cheng
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supporting information
p. 8194 - 8207
(2021/06/28)
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- METHODS AND COMPOSITIONS FOR TREATMENT OF CANCER
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In an aspect, the disclosure pertains to inhibitors of ANGPTL4; synthesis methods for making disclosed compounds; pharmaceutical compositions comprising disclosed compounds; methods of treating disorders of uncontrolled cellular proliferation, e.g., a cancer; and methods of treating a disease associated with an ANGPTL4 dysfunction using disclosed compounds and pharmaceutical compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.
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Paragraph 0139; 0140
(2021/07/30)
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- Structure-Activity Relationship Studies Reveal New Astemizole Analogues Active against Plasmodium falciparum in Vitro
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In the context of drug repositioning and expanding the existing structure-activity relationship around astemizole (AST), a new series of analogues were designed, synthesized, and evaluated for their antiplasmodium activity. Among 46 analogues tested, compounds 21, 30, and 33 displayed high activities against asexual blood stage parasites (PfNF54 IC50 = 0.025-0.043 μM), whereas amide compound 46 additionally showed activity against late-stage gametocytes (stage IV/V; PfLG IC50 = 0.6 ± 0.1 μM) and 860-fold higher selectivity over hERG (46, SI = 43) compared to AST. Several analogues displaying high solubility (Sol > 100 μM) and low cytoxicity in the Chinese hamster ovary (SI > 148) cell line have also been identified.
- Birkholtz, Lyn-Marie,Chibale, Kelly,Coertzen, Dina,Ferger, Richard,Kumar, Malkeet,Mambwe, Dickson,Njoroge, Mathew,Reader, Janette,Taylor, Dale,Van Der Watt, Mari?tte
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supporting information
p. 1333 - 1341
(2021/08/24)
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- Synthesis and anti-Plasmodium activity of benzimidazole analogues structurally related to astemizole
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A series of compounds structurally related to astemizole were designed and synthesized with the goal of determining their anti-Plasmodium activity. Several modifications of the astemizole structure, namely the removal of the 4-fluorobenzyl and/ or 4-methoxyphenethyl moieties, substitution of the benzene ring of the benzimidazole scaffold, replacement of the fluorine atom in the 4-fluorobenzyl group, and variation of the 4-aminopiperidine moiety, were explored. In vitro evaluation of the anti-Plasmodium activity of these compounds using the ItG strain showed that astemizole and some of its structurally similar derivatives have IC50 values in the nanomolar range and exhibit toxicity towards the parasite over Chinese ovarian hamster (CHO) cells with a selectivity as high as 200. The presence of a secondary cyclic amine at position 2 and substitution with chlorine at positions 4 and 5 in the benzimidazole moiety are two modifications that resulted in potent and selective antimalarials based on astemizole.
- Roman, Gheorghe,Crandall, Ian E.,Szarek, Walter A.
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p. 1795 - 1804
(2014/01/06)
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- Mepyramine-JNJ7777120-hybrid compounds show high affinity to hH 1R, but low affinity to hH4R
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In literature, a synergism between histamine H1 and H 4 receptor is discussed. Furthermore, it was shown, that the combined application of mepyramine, a H1 antagonist and JNJ7777120, a H 4 receptor ligand leads to a synergistic effect in the acute murine asthma model. Thus, the aim of this study was to develop new hybrid ligands, containing one H1 and one H4 pharmacophor, connected by an appropriate spacer, in order to address both, H1R and H 4R. Within this study, we synthesized nine hybrid compounds, which were pharmacologically characterized at hH1R and hH4R. The new compounds revealed (high) affinity to hH1R, but showed only low affinity to hH4R. Additionally, we performed molecular dynamic studies for some selected compounds at hH1R, in order to obtain information about the binding mode of these compounds on molecular level.
- Wagner, Eva,Wittmann, Hans-Joachim,Elz, Sigurd,Strasser, Andrea
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supporting information; scheme or table
p. 6274 - 6280
(2011/11/29)
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- Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part 2: Synthesis of potent αvβ3/αIIbβ3 dual antagonists
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We synthesized 4-aminopiperidine derivatives of our prototype integrin αvβ3 antagonist 1 in an attempt to increase the activity and water solubility. Introduction of one or two hydrophilic moieties into the central aromatic ring and/or the benzene ring at the C-terminus of 1 increased water solubility and enhanced inhibition of cell adhesion. The results of a structure-activity relationships (SAR) study indicated that the torsion angle between the central aromatic ring and the piperidine ring, and the acidity at the sulfonamide moiety, might be important for αvβ 3 receptor binding activity. Some of these compounds are novel and potent αvβ3/αIIbβ 3 dual antagonists with acceptable water solubility and a satisfactory early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile.
- Ishikawa, Minoru,Kubota, Dai,Yamamoto, Mikio,Kuroda, Chizuko,Iguchi, Maki,Koyanagi, Akihiro,Murakami, Shoichi,Ajito, Keiichi
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p. 2109 - 2130
(2007/10/03)
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- Substituted piperidine compounds useful as modulators of chemokine receptor activity
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The invention provides compounds of formula (I) wherein R1, R2, R3, R6, Z, Q, m, n, X1, X2, X3, X4 and T are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them, and their use in therapy, especially for the treatment of chemokine receptor related diseases and conditions
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Page/Page column 54
(2008/06/13)
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- Aminopiperidine derivates as integrin αvβ3 antagonists
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An objective of the present invention is to provide compounds having integrin αvβ3antagonistic activity, cell adhesion inhibitory activity, GP IIb/IIIa antagonistic activity, and/or human platelet aggregation inhibitory activity, and, therapeutic agents for treating cardiovascular diseases, angiogenesis-related diseases, cerebrovascular diseases and the like and for inhibiting platelet aggregation. The derivatives according to the present invention are compounds represented by formula (I) or pharmaceutically acceptable salts or solvates thereof: wherein A represents a five- to seven-membered heterocyclic group containing two nitrogen atoms or the like; D represents >NH2, >CH2or the like; X and Z represent CH or a nitrogen atom; R7and R8represent alkyl, halogen or the like; Q represents >C═O, >CH2or the like; R9represents H, alkyl, aralkyl or the like; R10represents H, alkynyl or the like; R11represents H, substituted amino or the like; R12represents H or alkyl; m is 0 to 5; n is 0 to 4; p and q are each 1 to 3; and r is 0 or 1.
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- Substituted 4-(1H-benzimidazol-2-yl-amino)piperidines useful for the treatment of allergic diseases
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The present invention relates to novel substituted piperidine derivatives of formula (1), stereoisomers thereof, and pharmaceutically acceptable salts thereof which are useful as histamine receptor antagonists and tachykinin receptor antagonist. Such antagonists are useful in the treatment of allergic rhinitis, including seasonal rhinitis and sinusitis; inflammatory bowel diseases, including Crohn's disease and ulcerative colitis; asthma; bronchitis; and emesis.
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- SUBSTITUTED N-METHYL-N-(4-(4-(1H-BENZIMIDAZOL-2-YL-AMINO) PIPERIDIN-1-YL)-2-(ARLYL) BUTYL) BENZAMIDES USEFUL FOR THE TREATMENT OF ALLERGIC DISEASES
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The present invention relates to novel substituted N-methyl-N-(4-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)-2-(aryl)butyl) benzamide derivatives of the formula: STR1 stereoisomers thereof, and pharmaceutically acceptable salts thereof which are useful as histamine receptor antagonists and tachykinin receptor antagonists. Such antagonists are useful in the treatment of allergic rhinitis, including seasonal rhinitis and sinusitis; inflammatory bowel diseases, including Crohn's disease and ulcerative colitis; asthma; bronchitis; and emesis.
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- Remarkably selective palladium-catalyzed amination process: Rapid assembly of multiamino based structures
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Palladium-catalyzed selective amination by a primary amine in the presence of a secondary amine provided up to >99:1 selectivity with high yields.
- Hong, Yaping,Senanayake, Chris H.,Xiang, Tingjian,Vandenbossche, Charles P.,Tanoury, Gerald J.,Bakale, Roger P.,Wald, Stephen A.
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p. 3121 - 3124
(2007/10/03)
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- Anti-allergic five membered heterocyclic ring containing N-(bicyclic heterocycyl)-4-piperidinamines
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Five membered heterocyclic ring containing N-(bicyclic heterocyclyl)-4-piperidinamines having histamine and serotonine antagonistic activity which compounds are useful agents in the treatment of allergic diseases.
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- New antihistaminic N-heterocyclic 4-piperidinamines. 1. Synthesis and antihistaminic activity of N-(4-piperidinyl)-1H-benzimidazol-2-amines
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The synthesis of a series N-(4-piperidinyl)-1H-benzimidazol-2-amines and the preliminary evaluation of their in vitro and in vivo antihistaminic activity are described. Cyclodesulfurization of (2-aminophenyl) thioureas with mercury(II) oxide resulted in 2-aminobenzimidazole intermediates, which were monoalkylated on the endo-nitrogen atom. After deprotection of the piperideine nitrogen atom with 48% aqueous hydrobromic acid solution, the title compounds were obtained by three different methods, viz. alkylation, reductive amination, or oxirane ring-opening reactions. The in vivo antihistaminic activity was evaluated by the compound 48/80 induced lethality test in rats and histamine-induced lethality test in guinea pigs after oral and/or subcutaneous administration. The duration of action, for a selected number of compounds, was studied in the guinea pig. The phenylethyl derivatives showed the most potent antihistamine properties after oral administration in both animal species.
- Janssens,Torremans,Janssen,Stokbroekx,Luyckx
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p. 1925 - 1933
(2007/10/02)
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- N-Heterocyclyl-4-piperidinamines
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Novel N-heterocyclyl-4-piperidinamines wherein said heterocyclic radical is an optionally substituted 1H-benzimidazol-2-yl or 3H-imidazo[4,5-b]pyridin-2-yl radical, said compounds being useful as antihistaminic agents.
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