- Water soluble prodrugs of the antitumor agent 3-[(3-amino-4-methoxy)phenyl]-2-(3,4,5-trimethoxyphenyl)cyclopent-2-ene-1-one
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Fourteen prodrugs of the antitumor agent 3-[(3-amino-4-methoxy)phenyl]-2-(3,4,5-trimethoxyphenyl)cyclopent-2-ene-1-one (1) were prepared to improve its water solubility and potency. These prodrugs include α-amino acid (1a-1h), aliphatic amino acid (1i-1l), phosphoramidate (1m), and phosphate (1n) derivatives. All of the prodrugs showed improved water solubility. A number of the amino acid prodrugs (1a, 1b, 1d-1f, 1h, 1j, and 1k) exhibited more potent antitumor activity compared to the parent compound (1). The phosphate prodrug 1n also offered a potent antitumor activity, but the phosphoramidate 1m did not show any antitumor activity in vivo. None of the prodrugs exhibited significant toxicities in mice. These results indicate that the design and preparation of the amino acid prodrugs (1a, 1b, 1d-1f, 1h, 1j, and 1k) and phosphate prodrug (1n) are beneficial for enhancing the antitumor activity of 1. The similar approaches may be used to improve water solubility and bioactivity of other poorly soluble aromatic amines.
- Nam, Nguyen-Hai,Kim, Yong,You, Young-Jae,Hong, Dong-Ho,Kim, Hwan-Mook,Ahn, Byung-Zun
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Read Online
- Preparation and characterization of a novel Al18F–NOTA–BZA conjugate for melanin-targeted imaging of malignant melanoma
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Melanin is an attractive target for the diagnosis and treatment of malignant melanoma. Previous studies have demonstrated the specific binding ability of benzamide moiety to melanin. In this study, we developed a novel18F-labeled NOTA–benzamide
- Chang, Chih-Chao,Chang, Chih-Hsien,Lo, Yi-Hsuan,Lin, Ming-Hsien,Shen, Chih-Chieh,Liu, Ren-Shyan,Wang, Hsin-Ell,Chen, Chuan-Lin
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Read Online
- Harnessing the anti-nociceptive potential of nk2 and nk3 ligands in the design of new multifunctional μ/δ-opioid agonist–neurokinin antagonist peptidomimetics
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Opioid agonists are well-established analgesics, widely prescribed for acute but also chronic pain. However, their efficiency comes with the price of drastically impacting side effects that are inherently linked to their prolonged use. To answer these liabilities, designed multiple ligands (DMLs) offer a promising strategy by co-targeting opioid and non-opioid signaling pathways involved in nociception. Despite being intimately linked to the Substance P (SP)/neurokinin 1 (NK1) system, which is broadly examined for pain treatment, the neurokinin receptors NK2 and NK3 have so far been neglected in such DMLs. Herein, a series of newly designed opioid agonist-NK2 or-NK3 antagonists is reported. A selection of reported peptidic, pseudo-peptidic, and non-peptide neurokinin NK2 and NK3 ligands were covalently linked to the peptidic μ-opioid selective pharma-cophore Dmt-DALDA (H-Dmt-D-Arg-Phe-Lys-NH2 ) and the dual μ/δ opioid agonist H-Dmt-D-Arg-Aba-βAla-NH2 (KGOP01). Opioid binding assays unequivocally demonstrated that only hybrids SBL-OPNK-5, SBL-OPNK-7 and SBL-OPNK-9, bearing the KGOP01 scaffold, conserved nanomo-lar range μ-opioid receptor (MOR) affinity, and slightly reduced affinity for the δ-opioid receptor (DOR). Moreover, NK binding experiments proved that compounds SBL-OPNK-5, SBL-OPNK-7, and SBL-OPNK-9 exhibited (sub)nanomolar binding affinity for NK2 and NK3, opening promising opportunities for the design of next-generation opioid hybrids.
- Ballet, Steven,Gadais, Charlène,Janecka, Anna,Martin, Charlotte,Neve, Jolien De,Piekielna-Ciesielska, Justyna
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supporting information
(2021/09/13)
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- HISTONE DEMETHYLASE INHIBITORS FOR TREATING CANCERS
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The present disclosure provides a new series of 8-hydroxyquinoline derivatives/analogs that are potent KDM4 inhibitors with high activity and selectivity against KDM4 enzymes. Also disclosed are the pharmaceutical compositions comprising such 8-hydroxyqui
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- PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia
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Dysregulated Histone Deacetylase (HDAC) activity across multiple human pathologies have highlighted this family of epigenetic enzymes as critical druggable targets, amenable to small molecule intervention. While efficacious, current approaches using non-selective HDAC inhibitors (HDACi) have been shown to cause a range of undesirable clinical toxicities. To circumvent this, recent efforts have focused on the design of highly selective HDACi as a novel therapeutic strategy. Beyond roles in regulating transcription, the unique HDAC6 (with two catalytic domains) regulates the deacetylation of α-tubulin; promoting growth factor-controlled cell motility, cell division, and metastatic hallmarks. Recent studies have linked aberrant HDAC6 function in various hematological cancers including acute myeloid leukaemia and multiple myeloma. Herein, we report the discovery, in vitro characterization, and biological evaluation of PTG-0861 (JG-265), a novel HDAC6-selective inhibitor with strong isozyme-selectivity (~36× ) and low nanomolar potency (IC50 = 5.92 nM) against HDAC6. This selectivity profile was rationalized via in silico docking studies and also observed in cellulo through cellular target engagement. Moreover, PTG-0861 achieved relevant potency against several blood cancer cell lines (e.g. MV4-11, MM1S), whilst showing limited cytotoxicity against non-malignant cells (e.g. NHF, HUVEC) and CD-1 mice. In examining compound stability and cellular permeability, PTG-0861 revealed a promising in vitro pharmacokinetic (PK) profile. Altogether, in this study we identified a novel and potent HDAC6-selective inhibitor (~4× more selective than current clinical standards – citarinostat, ricolinostat), which achieves cellular target engagement, efficacy in hematological cancer cells with a promising safety profile and in vitro PK.
- Bukhari, Shazreh,Cabral, Aaron D.,Gawel, Justyna M.,Gunning, Patrick T.,Israelian, Johan,Manaswiyoungkul, Pimyupa,Nawar, Nabanita,Olaoye, Olasunkanmi O.,Radu, Tudor B.,Raouf, Yasir S.,Sedighi, Abootaleb,Shouksmith, Andrew E.,Sina, Diana,Toutah, Krimo,de Araujo, Elvin D.
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- Antiglioma Activity of Aryl and Amido-Aryl Acetamidine Derivatives Targeting iNOS: Synthesis and Biological Evaluation
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Nitric oxide is an important inflammation mediator with a recognized role in the development of different cancers. Gliomas are primary tumors of the central nervous system with poor prognosis, and the expression of the inducible nitric oxide synthase correlates with the degree of malignancy, changes in vascular reactivity, and neo-angiogenesis. Therefore, targeting the nitric oxide biosynthesis appears as a potential strategy to impair glioma progression. In the present work a set of aryl and amido-aryl acetamidine derivatives were synthesized to obtain new potent and selective inducible nitric oxide synthase inhibitors with improved physicochemical parameters with respect to the previously published molecules. Compound 17 emerged as the most promising inhibitor and was evaluated on C6 rat glioma cell line, showing antiproliferative effects and high selectivity over astrocytes.
- Maccallini, Cristina,Arias, Fabio,Gallorini, Marialucia,Amoia, Pasquale,Ammazzalorso, Alessandra,De Filippis, Barbara,Fantacuzzi, Marialuigia,Giampietro, Letizia,Cataldi, Amelia,Camacho, María Encarnación,Amoroso, Rosa
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supporting information
p. 1470 - 1475
(2020/07/31)
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- CHIMERIC COMPOUNDS AND METHODS OF MANAGING NEUROLOGICAL DISORDERS OR CONDITIONS
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This disclosure relates to chimeric compounds and methods for managing neurological conditions. In certain embodiments, the compound comprises a chemical structure of a monoamine reuptake inhibitor conjugated to a chemical structure of a histone deacetyla
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Page/Page column 45
(2020/09/12)
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- Acid-Stable Ester Linkers for the Solid-Phase Synthesis of Immobilized Peptides
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A series of N-terminally Fmoc-protected linkers of the general formula Fmoc-X?CO?O?Y?COOH have been prepared, where X is ?NH?CH2?CH2- or -p-(aminomethyl)phenyl- and Y is ?(CH2)n? (n is 1 or 4) or -p-(methyl)phenyl-. These linkers can easily be covalently attached via their C-terminal carboxyl group to a resin bearing a free amino group. After cleavage of the N-terminal Fmoc group, the linkers can be extended by standard solid-phase peptide synthesis techniques. These ester linkers are acid-stable and resistant to the base-mediated diketopiperazine formation that often occurs during the synthesis of ester-bound peptides; they are stable at neutral pH in aqueous buffers for days but can be effectively cleaved with 0.1 m NaOH or aq. ammonia within minutes or hours, respectively. These properties make these ester handles well suited for use as linkers for the solid-phase peptide synthesis of immobilized peptides when the stable on-resin immobilization of the peptides and the testing of their biological properties in aqueous buffers at neutral pH are necessary.
- Budě?ínsky, Milo?,Jirá?ek, Ji?í,Mitrová, Katarína,Pícha, Jan
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p. 1297 - 1306
(2020/07/04)
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- Synthesis, biological evaluation and molecular modeling study of 2-amino-3,5-disubstituted-pyrazines as Aurora kinases inhibitors
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Serine/threonine protein kinases Aurora A, B, and C play essential roles in cell mitosis and cytokinesis, and a number of Aurora kinase inhibitors have been evaluated in the clinic. Herein we report the synthesis and their antiproliferation of 3,5-disubstituted-2-aminopyrazines as kinases inhibitors. Amongst, 4-((3-amino-6- (3,5-dimethylisoxazol-4-yl)pyrazin-2-yl)oxy)-N-(3-chlorophenyl) benzamide (12Aj) exhibited the strongest antiproliferative activities against U38, HeLa, HepG2 and LoVo cells with IC50 values were 11.5 ± 3.2, 1.34 ± 0.23, 7.30 ± 1.56 and 1.64 ± 0.48 μM, as well as inhibited Aurora A and B with the IC50 values were 90 and 152 nM, respectively. Molecular docking studies indicated that 12Aj appeared to form stable hydrogen bonds with either Aurora A or Aurora B. Furthermore, 12Aj arrested HeLa cell cycle in G2/M phase by regulating protein levels of cyclinB1 and cdc2. In addition, the bioinformatics prediction further revealed that 12Aj possessed good drug likeness using SwissADME. These results suggested that 12Aj was worthy of future development of potent anticancer agents as pan-Aurora kinases.
- Bo, Yong-Xin,Chen, Shi-Wu,Hao, Shu-Yi,Wang, Xing-Rong,Xiang, Rong,Xu, Yu
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- INHIBITORS OF INDOLEAMINE 2,3-DIOXYGENASE AND METHODS OF THEIR USE
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The present invention provides a compound of formula (II): an inhibitor of indoleamine 2,3-dioxygenase (IDO), which may be used as medicaments for the treatment of proliferative disorders, such as cancer, viral infections and/or autoimmune diseases. Its prodrugs are disclosed.
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Page/Page column 157; 158
(2019/07/20)
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- Design, synthesis and biological research of novel N-phenylbenzamide-4-methylamine acridine derivatives as potential topoisomerase I/II and apoptosis-inducing agents
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A series of novel N-phenylbenzamide-4-methylamine acridine derivatives were designed and synthesized based initially on the structure of amsacrine (m-AMSA). Molecular docking suggested that the representative compound 9a had affinity for binding DNA topoisomerase (Topo) II, which was comparable with that of m-AMSA, and furthermore that 9a could have preferential interactions with Topo I. After synthesis of 9a and analogues 9b-9f, these were all tested in vitro and the synthesized compounds displayed potent antiproliferative activity against three different cancer cell lines (K562, CCRF-CEM and U937). Among them, compounds 9b, 9c and 9d exhibiting the highest activity with IC50 value ranging from 0.82 to 0.91 μM against CCRF-CEM cells. In addition, 9b and 9d also showed high antiproliferative activity against U937 cells, with IC50 values of 0.33 and 0.23 μM, respectively. The pharmacological mechanistic studies of these compounds were evaluated by Topo I/II inhibition, western blot assay and cell apoptosis detection. In summary, 9b effectively inhibited the activity of Topo I/II and induced DNA damage in CCRF-CEM cells and, moreover, significantly induced cell apoptosis in a concentration-dependent manner. These observations provide new information and guidance for the structural optimization of more novel acridine derivatives.
- Zhang, Bin,Dou, Zhende,Xiong, Zheng,Wang, Ning,He, Shan,Yan, Xiaojun,Jin, Haixiao
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supporting information
(2019/10/28)
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- 4-methylaminoacridine-N-phenylbenzamide compound and preparation method and application thereof
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The invention discloses a 4-aminomethylacridine-N-phenylbenzamide compound and a preparation method and application thereof. The compound is characterized in that the compound is a compound with a structural formula shown in the formula I or a pharmaceutically acceptable salt, ester or solvate of the compound with the structural formula shown in the formula I, wherein R1 is H, OCH3, OCH2CH3, Cl, Br, CF3, NO2 or a linear alkyl group with 1 to 5 carbon atoms, R2 is H, OCH3, OCH2CH3, Cl, Br, CF3, NO2 or a linear alkyl group with 1 to 5 carbon atoms, R3 is H, OCH3, OCH2CH3, Cl, Br, CF3, NO2 or a linear alkyl group with 1 to 5 carbon atoms, and n = 1, 2, 3 or 4, the advantages are that the compound can effectively inhibit the activity of DNA topoisomerases, inhibits the proliferation of eukaryotic tumor cells, and prevents and / or treats tumors.
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Paragraph 0021; 0023
(2019/11/14)
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- TARGETING COMPOUNDS
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The disclosure provides, at least in part, liver, intestine and/or kidney-targeting compounds and their use in treating liver, intestine and/or kidney disorders, such as non-alcoholic steatohepatitis, alcoholic steatohepatitis, hepatocellular carcinoma, liver cirrhosis, and hepatitis B; and/or chronic kidney disease, glomerular disease such as IGA nephropathy, lupus nephritis, or polycystic kidney disease. The compounds are contemplated to have activity against methionyl aminopeptidase 2.
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Paragraph 0197
(2019/07/19)
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- Optimization of Novel 1-Methyl-1 H-Pyrazole-5-carboxamides Leads to High Potency Larval Development Inhibitors of the Barber's Pole Worm
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A phenotypic screen of a diverse library of small molecules for inhibition of the development of larvae of the parasitic nematode Haemonchus contortus led to the identification of a 1-methyl-1H-pyrazole-5-carboxamide derivative with an IC50 of 0.29 μM. Medicinal chemistry optimization targeted modifications on the left-hand side (LHS), middle section, and right-hand side (RHS) of the scaffold in order to elucidate the structure-activity relationship (SAR). Strong SAR allowed for the iterative and directed assembly of a focus set of 64 analogues, from which compound 60 was identified as the most potent compound, inhibiting the development of the fourth larval (L4) stage with an IC50 of 0.01 μM. In contrast, only 18% inhibition of the mammary epithelial cell line MCF10A viability was observed, even at concentrations as high as 50 μM.
- Le, Thuy G.,Kundu, Abhijit,Ghoshal, Atanu,Nguyen, Nghi H.,Preston, Sarah,Jiao, Yaqing,Ruan, Banfeng,Xue, Lian,Huang, Fei,Keiser, Jennifer,Hofmann, Andreas,Chang, Bill C. H.,Garcia-Bustos, Jose,Jabbar, Abdul,Wells, Timothy N. C.,Palmer, Michael J.,Gasser, Robin B.,Baell, Jonathan B.
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p. 10875 - 10894
(2019/01/04)
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- Systematic variation of the benzenesulfonamide part of the GluN2A selective NMDA receptor antagonist TCN-201
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GluN2A subunit containing N-methyl-D-aspartate receptors (NMDARs) are highly involved in various physiological processes in the central nervous system, but also in some diseases, such as anxiety, depression and schizophrenia. However, the role of GluN2A subunit containing NMDARs in pathological processes is not exactly elucidated. In order to obtain potent and selective inhibitors of GluN2A subunit containing NMDARs, the selective negative allosteric modulator 2 was systematically modified at the benzenesulfonamide part. The activity of the test compounds was recorded in two electrode voltage clamp experiments using Xenopus laevis oocytes expressing exclusively NMDARs with GluN1a and GluN2A subunits. It was found that halogen atoms in 3-position of the benzenesulfonamide part result in high GluN2A antagonistic activity. With an IC50 value of 204?nM the 3-bromo derivative 5i (N-{4-[(2-benzoylhydrazino)carbonyl]benzyl}-3-bromobenzenesulfonamide) has 2.5-fold higher antagonistic activity than the lead compound 2 and represents our new lead compound.
- Müller, Sebastian L.,Schreiber, Julian A.,Schepmann, Dirk,Strutz-Seebohm, Nathalie,Seebohm, Guiscard,Wünsch, Bernhard
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supporting information
p. 124 - 134
(2017/02/23)
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- Chemoselective Installation of Amine Bonds on Proteins through Aza-Michael Ligation
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Chemical modification of proteins is essential for a variety of important diagnostic and therapeutic applications. Many strategies developed to date lack chemo- and regioselectivity as well as result in non-native linkages that may suffer from instability in vivo and adversely affect the protein's structure and function. We describe here the reaction of N-nucleophiles with the amino acid dehydroalanine (Dha) in a protein context. When Dha is chemically installed in proteins, the addition of a wide-range N-nucleophiles enables the rapid formation of amine linkages (secondary and tertiary) in a chemoselective manner under mild, biocompatible conditions. These new linkages are stable at a wide range of pH values (pH 2.8 to 12.8), under reducing conditions (biological thiols such as glutathione) and in human plasma. This method is demonstrated for three proteins and is shown to be fully compatible with disulfide bridges, as evidenced by the selective modification of recombinant albumin that displays 17 structurally relevant disulfides. The practicability and utility of our approach is further demonstrated by the construction of a chemically modified C2A domain of Synaptotagmin-I protein that retains its ability to preferentially bind to apoptotic cells at a level comparable to the native protein. Importantly, the method was useful for building a homogeneous antibody-drug conjugate with a precise drug-to-antibody ratio of 2. The kinase inhibitor crizotinib was directly conjugated to Dha through its piperidine motif, and its antibody-mediated intracellular delivery results in 10-fold improvement of its cancer cell-killing efficacy. The simplicity and exquisite site-selectivity of the aza-Michael ligation described herein allows the construction of stable secondary and tertiary amine-linked protein conjugates without affecting the structure and function of biologically relevant proteins.
- Freedy, Allyson M.,Matos, Maria J.,Boutureira, Omar,Corzana, Francisco,Guerreiro, Ana,Akkapeddi, Padma,Somovilla, Víctor J.,Rodrigues, Tiago,Nicholls, Karl,Xie, Bangwen,Jiménez-Osés, Gonzalo,Brindle, Kevin M.,Neves, André A.,Bernardes, Gon?alo J. L.
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supporting information
p. 18365 - 18375
(2017/12/27)
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- AMINONAPHTHOQUINONE COMPOUNDS FOR TREATMENT AND/OR PREVENTION OF FIBROSIS DISEASES
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The present disclosure relates to the use of a compound of Formula (I) as described herein and its effective dose in the prevention and/or treatment of fibrosis diseases. The compound can effectively prevent and/or treat a fibrosis disease without cytotox
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Paragraph 00103; 00104
(2017/06/12)
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- From Sphingosine Kinase to Dihydroceramide Desaturase: A Structure-Activity Relationship (SAR) Study of the Enzyme Inhibitory and Anticancer Activity of 4-((4-(4-Chlorophenyl)thiazol-2-yl)amino)phenol (SKI-II)
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The sphingosine kinase (SK) inhibitor, SKI-II, has been employed extensively in biological investigations of the role of SK1 and SK2 in disease and has demonstrated impressive anticancer activity in vitro and in vivo. However, interpretations of results u
- Aurelio, Luigi,Scullino, Carmen V.,Pitman, Melissa R.,Sexton, Anna,Oliver, Victoria,Davies, Lorena,Rebello, Richard J.,Furic, Luc,Creek, Darren J.,Pitson, Stuart M.,Flynn, Bernard L.
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p. 965 - 984
(2016/02/23)
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- Chloride transport activities of trans- and cis-amide-linked bisureas
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Of the bisurea compounds linked through trans- and cis-benzanilide spacers, the cis-amide derivatives were found to be effective in chloride transport, using which a stimuli-responsive mobile carrier was devised. This journal is
- Park, Eun Bit,Jeong, Kyu-Sung
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supporting information
p. 9197 - 9200
(2015/06/02)
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- Unusual orthogonality in the cleavage process of closely related chelating protecting groups for carboxylic acids by using different metal ions
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Three structurally related relay protecting groups for carboxylic acids that are based on chelating amines have been developed. These protecting groups can easily be introduced by coupling the carboxylic acid and the corresponding amine in the presence of 2-(1Hbenzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU). In addition to being stable to a whole array of reaction conditions, these protecting groups are also stable under acidic and basic conditions, allowing them to be used in combination with the ester protection of carboxylic acids. The cleavage of these protecting groups is activated by the chelation of metal ions, involving an unusual coordination of the amide nitrogen. Despite their similarity, cleavage of these protecting groups is possible in both a stepwise and an orthogonal fashion by applying different metal salts.
- Mundinger, Stephan,Jakob, Uwe,Bannwarth, Willi
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supporting information
p. 1258 - 1262
(2014/04/03)
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- Design, synthesis and biological evaluation of 4′-demethyl-4-deoxypodophyllotoxin derivatives as novel tubulin and histone deacetylase dual inhibitors
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A new class of 4′-demethyl-4-deoxypodophyllotoxin derivatives has been designed and synthesized as tubulin-HDAC dual inhibitors. Biological evaluation of these hybrids included the inhibitory activity of HDAC, in vitro cell cycle analysis in HCT-116 cells as well as cytotoxicity against two cancer cell lines (A549 and HCT116). The distance and angle between the HDAC capping group and the zinc binding group were systematically varied. Compounds 14a and 14c showed most potent dual inhibitory activity and powerful antiproliferative activity on HCT116 and A549 cell lines. This journal is
- Zhang, Xuan,Zhang, Jie,Su, Mingbo,Zhou, Yubo,Chen, Yi,Li, Jia,Lu, Wei
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p. 40444 - 40448
(2014/12/11)
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- PROTEIN KINASE INHIBITORS AND METHODS OF TREATMENT
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The present invention relates to chemical compounds of formula (I) and methods for their use and preparation. In particular, the invention relates to substituted pyrazolo[3,4-d]pyrimidine based compounds which can be used in treating proliferative disorders, use of these compounds in methods of therapy and the manufacture of medicaments as well as compositions containing these compounds.
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Page/Page column 57
(2012/02/01)
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- HETEROCYCLIC COMPOUND AND HEMATOPOIETIC STEM CELL AMPLIFIER
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An expansion agent for hematopoietic stem cells and/or hematopoietic progenitor cells useful for improvement in the efficiency of gene transfer into hematopoietic stem cells for gene therapy useful for treatment of various disorders is provided. An expansion agent for hematopoietic stem cells and/or hematopoietic progenitor cells containing a compound represented by the formula (I) (wherein X, Y, Z, Ar1, R1, R2, R3, R4, R5, R6 and R7 are as defined in the description), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof, which can expand hematopoietic stem cells and/or hematopoietic progenitor cells.
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Page/Page column 45
(2012/04/23)
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- FUSED HETEROCYCLIC COMPOUNDS AND THROMBOPOIETIN RECEPTOR ACTIVATORS
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Fused heterocyclic compounds useful for prevention, treatment or improvement of diseases against which activation of the thrombopoietin receptor is effective are provided. A compound represented by the formula (I) (wherein R1 is an aryl group fused to a saturated ring or the like, A, B, L1, R2, L2, L3, Y, L4, R3 and X are defined in the description), a tautomer, prodrug or a pharmaceutically acceptable salt of the compound or a solvate thereof.
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Page/Page column 35
(2012/08/28)
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- Benzothiazinones: A novel class of adenosine receptor antagonists structurally unrelated to xanthine and adenine derivatives
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2-(Acyl)amino-4H-3,1-benzothiazin-4-ones and related thienothiazinones were identified as structurally novel antagonists at adenosine receptors (ARs). 6-Methyl-2-benzoylamino-4H-3,1-benzothiazin-4-one (10d) was found to be a balanced AR antagonist with affinity for all human (h) subtypes (Ki hA1 65.6 nM; hA2A 120 nM; hA2B 360 nM; hA 3 30.4 nM), while in rat (r), 10d was a highly potent A 1-selective antagonist (rA1 7.7 nM; rA2A 546 nM; rA2B 679 nM, rA3 >10000 nM). 2-(4- Methylbenzoylamino)-4H-3,1-benzothiazin-4-one (10g) was found to be a potent antagonist at human A2A (68.8 nM) and A3 ARs (23.0 nM) with high selectivity versus the other human AR subtypes. In contrast to A 1 and A3 ARs, A2A and A2B ARs tolerated bulky 2-acyl substituents. tert-Butyl (4-oxo-4H-3,1-benzothiazin-2- ylcarbamoyl)benzylcarbamate (15g, Ki hA2B 186 nM; hA 2A 603 nM) and 4-(4-benzylpiperazine-1-carbonyl)-N-(4-oxo-4H-3,1- benzothiazin-2-yl)benzamide (15k, hA2A 69.5 nM; hA2B 178 nM) were highly selective versus the other AR subtypes. 2-Acylamino-3,1- benzothiazin-4-ones represent novel scaffolds suitable for the development of potent and selective AR antagonists for each of the four receptor subtypes.
- Gütschow, Michael,Schlenk, Miriam,G?b, Jürgen,Paskaleva, Minka,Alnouri, Mohamad Wessam,Scolari, Silvia,Iqbal, Jamshed,Müller, Christa E.
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experimental part
p. 3331 - 3341
(2012/06/04)
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- COFERONS AND METHODS OF MAKING AND USING THEM
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The present invention is directed to a monomer useful in preparing therapeutic compounds. The monomer includes one or more pharmacophores which potentially binds to a target molecule with a dissociation constant of less than 300 μM and a linker element connected to the pharmacophore. The linker element has a molecular weight less than 500 daltons, is connected, directly or indirectly through a connector, to the pharmacophore.
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Page/Page column 174
(2012/12/13)
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- HISTONE DEACETYLASE INHIBITORS
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The disclosure provides compounds of formula I and methods for preparation thereof. The compounds act as inhibitor of histone deacetylase.
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Page/Page column 18; 19
(2012/05/04)
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- Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1α interaction
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E3 ubiquitin ligases, which bind protein targets, leading to their ubiquitination and subsequent degradation, are attractive drug targets due to their exquisite substrate specificity. However, the development of small-molecule inhibitors has proven extrao
- Buckley, Dennis L.,Van Molle, Inge,Gareiss, Peter C.,Tae, Hyun Seop,Michel, Julien,Noblin, Devin J.,Jorgensen, William L.,Ciulli, Alessio,Crews, Craig M.
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supporting information; experimental part
p. 4465 - 4468
(2012/04/23)
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- KINASE INHIBITORS
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The present invention relates to compounds of formula (I): wherein A= formula: (a) or formula: (b); X is oxygen or methylene; Y is C3-6 alkyl or aryl; Z is oxygen or C1-3 alkyl; R1 is hydrogen or C1-3 alkyl; Rs
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Page/Page column 29; 31
(2011/04/14)
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- BENZAMIDE DERIVATIVES AND THEIR USE AS HSP90 INHIBTORS
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The invention provides a compound which is (a) a phenylamide derivative of formula (I) or a tautomer thereof, or (b) a pharmaceutically acceptable salt, N-oxide, hydrate, prodrug or solvate thereof: wherein R1, R2, R3, R4, R5, R6 and R7 are as defined herein. The compounds are useful in the treatment of diseases mediated by HSP90.
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Page/Page column 65-66
(2012/01/05)
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- HISTONE DEACETYLASE INHIBITORS
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The disclosure provides compounds of formula I and methods for preparation thereof. The compounds act as inhibitor of histone deacetylase.
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Page/Page column 49; 50
(2011/04/13)
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- NEW BRADYKININ B1 ANTAGONISTS
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The invention relates to compounds of formula (I) where in R1, R1a, R1b, R2, R3 and X, X1, X2, X3 have the meaning as cited in the description and the claims. Said compounds are useful as Bradykinin B1 antagonists. The invention also relates to pharmaceutical compositions, the preparation of such compounds as well as the production and use as medicament.
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Page/Page column 68
(2010/04/03)
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- Collection of traceable compounds and uses thereof
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The use of a collection of compounds of general formula (I), wherein: n is 0 or 1; p represents an integer between 1 and 6; r represents an integer between 1 and 12; R1 and R′1 represent in particular a hydrogen atom; R2 represents an amino acid side chain or an amino acid derivative; R3 represents a group derived from a carboxylic acid, bearing a basic entity; R4 represents in particular an alkyl group containing 1 to 10 carbon atoms; and A represents a hydrogen atom, a protecting group or a tracing group, in particular a fluorophor, a coloring agent or a quencher, for determining, through binding studies, ligands of receptors whose ligand is unknown or whose ligand useful for carrying out specific affinity binding assays is unknown.
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- Tripodal tris-tacn and tris-dpa platforms for assembling phosphate-templated trimetallic centers
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Multidentate tripodal ligands, N(CH2-m-C6H 4-CH2tacn)3 (L1) and N(CH2-o-C 6H4-CH2N(CH2py)2) 3 (L2), have been devised for assembling high-nuclearity metal clusters. By using the same tripodal platform with different ligand appendages, either triazacyclononanes or dipicolylamines, and functionalizing either the ortho or the meta positions on the tris(xylyl) linker arms, discrete trimetal phosphate units of relevance to phosphate-metabolizing trimetallic centers in biology were prepared. Four such compounds, [(CuIICl) 3(HPO4)L1](PF6) (1), [(CuIICl) 3(HAsO4)L1](PF6) (2), Na2[Mn III6MnII2(H2O) 2(HPO4)6(PO4)4(L1) 2] (3), and [CoII3(H2PO 4)Cl2(MeCN)L2](PF6)3 (4), all containing three metal centers bound to a central phosphate or arsenate unit bridging oxygen atoms, have been synthesized and structurally characterized. These results demonstrate the propensity of this novel tripodal ligand platform, in the presence of phosphate or arsenate, to assemble {M3(EO 4)} units and thus structurally mimic trimetallic active sites of proteins involved in phosphate metabolism. Reactivity studies reveal that the tricopper complex 1 is more efficient than monocopper analogues in catalyzing the hydrolysis of 4-nitrophenyl phosphate.
- Cao, Rui,Mueller, Peter,Lippard, Stephen J.
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supporting information; experimental part
p. 17366 - 17369
(2011/02/23)
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- NOVEL HISTONE DEACETYLASE INHIBITORS
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Provided herein are novel, stilbene like compounds of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, metabolites, prodrugs, solvates, pharmaceutically acceptable salts and compositions thereof. These compounds can inhibit HDACs and are useful as a therapeutic or ameliorating agent for diseases that are involved in cellular growth such as WO 2009/047615 A2 malignant tumors, autoimmune diseases, skin diseases, infections, inflammation, etc.
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Page/Page column 11
(2010/09/07)
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- Basic techniques of working on a solid phase: From ABC of the peptide synthesis to libraries of non-natural amino acids
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Libraries of hardly available amino acids bearing a heteroaromatic ring (2-pyrimidyl, substituted 2-pyridyl or 2-thiazolyl) at the amino group were prepared using solid-phase synthesis on various resins. The synthesized compounds are structurally similar to some known antidiabetic drugs. The paper combines features of a review (elementary introduction to the solid-phase synthesis methodology and technique for beginners and selected methods from peptide chemistry) and step-by-step experimental protocols (tested by the authors) useful as a methodic tool. The presented protocols (immobilization and modification of amino acids, placing and removal of common protective groups) require no sophisticated equipment and may be useful as pictorial introductory tasks for students education. Pleiades Publishing, Ltd., 2010.
- Babaev,Ermolat'ev
-
experimental part
p. 2572 - 2589
(2011/04/15)
-
- NOVEL HISTONE DEACETYLASE INHIBITORS
-
Provided herein are novel, stilbene like compounds of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, metabolites, prodrugs, solvates, pharmaceutically acceptable salts and compositions thereof. These compounds can inhibit HDACs and are useful as a therpeautic or ameliorating agent for diseases that are involved in cellular growth such as malignant tumors, autoimmune diseases, skin diseases, infections, inflammation, etc.
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Page/Page column 24
(2009/05/30)
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- NOVEL 2-QUINOLONE DERIVATIVE
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A compound represented by the formula (1) or a pharmaceutically acceptable salt thereof which has a therapeutic or prophylactic effect on an SNS-related disease such as neuropathic pain. (1) wherein R1 and R2 independently represent
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Page/Page column 50
(2008/06/13)
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- HYDROXAMATES AS INHIBITORS OF HISTONE DEACETYLASE
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Compounds of formula (I), and salts, N-oxides, hydrates and solvates thereof are histone deacetylase inhibitors and are useful in the treatment of cell proliferative diseases, including cancers: wherein Q, V and W independently represent -N= or -C=; B is
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-
Page/Page column 58; 59-60
(2008/12/05)
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- HDAC INHIBITORS
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Compounds of formula (I) inhibit HDAC activity, wherein A, B and D independently represent =C- or =N-; W is a divalent radical -CH=CH- or CH2CH2-; R1 is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular carboxyesterase enzymes to a carboxylic acid group; R2 is the side chain of a natural or non-natural alpha amino acid; z is 0 or 1; and Y, L1, and X1 are as defined in the claims.
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Page/Page column 57-58
(2008/06/13)
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- An unexpected triethylsilane-triggered rearrangement of thioaurones to thioflavonols under SPPS conditions
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Thioaurones are converted to a mixture of thiaindenes and thioflavonols when exposed to reaction conditions employed in SPPS, that is, treatment with trifluoroacetic acid in the presence of triethylsilane.
- Varedian, Miranda,Langer, Vratislav,Bergquist, Jonas,Gogoll, Adolf
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supporting information; experimental part
p. 6033 - 6035
(2009/04/11)
-
- Chemistry and folding of photomodulable peptides - Stilbene and thioaurone-type candidates for conformational switches
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Optimized synthetic strategies for the preparation of photoswitchable molecular scaffolds based on stilbene or on thioaurone chromophores and their conformationally directing properties, as studied by computations and by NMR spectroscopy, are addressed. For the stilbene peptidomimetics 1, 2 and 3, the length of connecting linkers between the chromophore and the peptide strands was varied, resulting in photochromic dipeptidomimetics with various flexibility. Building blocks of higher rigidity, based on para-substituted thioaurone (4 and 6) and meta-substituted thioaurone chromophores (5 and 7) are shown to have a stronger conformationally directing effect. Design, synthesis, theoretical and experimental conformational analyses are presented.
- Erdelyi, Mate,Varedian, Miranda,Skoeld, Christian,Niklasson, Ida B.,Nurbo, Johanna,Persson, Asa,Bergquist, Jonas,Gogoll, Adolf
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experimental part
p. 4356 - 4373
(2009/02/07)
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- Polyaminohydroxamic acids and polyaminobenzamides as isoform selective histone deacetylase inhibitors
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A series of polyaminohydroxamic acids (PAHAs) and polyaminobenzamides (PABAs) were synthesized and evaluated as isoform-selective histone deacetylase (HDAC) inhibitors. These analogues contain a polyamine chain to increase affinity for chromatin and facil
- Varghese, Sheeba,Senanayake, Thulani,Murray-Stewart, Tracey,Doering, Kim,Fraser, Alison,Casero Jr., Robert A.,Woster, Patrick M.
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p. 2447 - 2456
(2008/12/22)
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- TETRAPEPTIDE INHIBITORS OF BETA-SECRETASE
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Statine-derived peptide inhibitors of the β-secretase enzyme are provided which are useful in the treatment of Alzheimer's disease and other diseases characterized by deposition of Aβ peptide in a mammal. The compounds of the invention provide useful meth
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Page/Page column 11; 24-25
(2008/06/13)
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- ENZYME INHIBITORS
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Compounds of formula (I) are inhibitors of histone deacetylase activity, and are useful in the treatment of, for example, cancers, wherein R1 is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular carboxyesterase enzymes to a carboxylic acid group; R2is the side chain of a natural or non-natural alpha amino acid; Y is a bond, -C(=O)-, -S(=O)2-, -C(=O)O-, -C(O)NR3-, -C(=S)-NR3 , -C(=NH)NR3 or -S(=O)2NR3- wherein R3 is hydrogen or optionally substituted C1-C6 alkyl; L1 is a divalent radical of formula -(Alk1)m(Q)n(Alk2)p- wherein m, n and p are independently 0 or 1 , Q is (i) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5 - 13 ring members, or (ii), in the case where both m and p are 0, a divalent radical of formula -X2-Q1- or -Q1-X2- wherein X2 is -O-, S- or NRA- wherein RA is hydrogen or optionally substituted C1-C3 alkyl, and Q1 is an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5 - 13 ring members, AIk1 and AIk2 independently represent optionally substituted divalent C3-C7 cycloalkyl radicals, or optionally substituted straight or branched, C1-C6 alkylene, C2-C6 alkenylene ,or C2-C6 alkynylene radicals which may optionally contain or terminate in an ether (-O-), thioether (-S-) or amino (-NRA-) link wherein RA is hydrogen or optionally substituted C1-C3 alkyl; X1 represents a bond; -C(=O); or -S(=O)2-; -NR4C(=O)-, -C(=O)NR4-, -NR4C(=O)NR5- , -NR4S(=O)2-, or -S(=O)2NR4-wherein R4 and R5 are independently hydrogen or optionally substituted C1-C6 alkyl; z is 0 or 1 ; A represents an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system wherein the radicals R1R2NH-Y-L1-X1-[CH2]Z- and HONHCO-[LINKER]- are attached different ring atoms; and -[Linker]- represents a divalent linker radical linking a ring atom in A with the hydroxamic acid group CONHOH, the length of the linker radical, from the terminal atom linked to the ring atom of A to the terminal atom linked to the hydroxamic acid group, is equivalent to that of an unbranched saturated hydrocarbon chain of from 3-10 carbon atoms.
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Page/Page column 147
(2008/06/13)
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- ANTIANGIOGENIC DRUG TO TREAT CANCER, ARTHRITIS AND RETINOPATHY
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Compounds having Formula (I) or pharmaceutically acceptable salts or prodrugs thereof, are useful for treating pathological states which arise from or are exacerbated by angiogenesis. The invention also relates to pharmaceutical compositions comprising th
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Page/Page column 12
(2010/11/24)
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- Pyrrolobenzodiazepine pyridine carboxamides and derivatives as follicle-stimulating hormone receptor antagonists
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This invention provides pyrrolobenzodiazepine pyridine carboxamides selected from those of Formula (1), which act as follicle stimulating hormone receptor antagonists. The invention also provides pharmaceutical compositions and methods of treatment utilizing the compounds of Formulae (1) and (2).
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Page/Page column 50
(2010/11/25)
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- Structure-based optimization of phenylbutyrate-derived histone deacetylase inhibitors
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Previously, we developed a strategy to develop a novel class of histone deacetylase (HDAC) inhibitors by tethering short-chain fatty acids with Zn 2+-chelating motifs, which led to N-hydroxy-4-(4-phenylbutyryl-amino) benzamide (HTPB), a hydroxa
- Lu, Qiang,Wang, Da-Sheng,Chen, Chang-Shi,Hu, Yuan-Dong,Chen, Ching-Shih
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p. 5530 - 5535
(2007/10/03)
-
- AMINE COMPOUNDS AND USE THEREOF
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It is intended to provide novel amine compounds which are efficacious against diseases such as infection with HIV virus, rheumatism and cancer metastasis. Namely, amine compounds represented by the following general formula (1):In a typical case, A1 and A2 represent each an optionally substituted monocyclic or polycyclic aromatic heterocycle; W represents cyclic C3-10 alkylene, an optionally substituted monocyclic or polycyclic aromatic heterocycle, a monocyclic or polycyclic aromatic ring or a partly saturated polycyclic aromatic ring; X represents O, CH2, C(=O) or NR11; and D is a group represented by the following general formula (4) or (6).-Q-Y-BIn the formula (6), Q represents a single bond, S, O or NR12; and Y is a group represented by the following general formula (7). z represents an optionally substituted monocyclic or polycyclic aromatic ring. In the formula (6), B represents NR25R26. In the above formulae, R1 to R26 each represents hydrogen, alkyl, alkenyl or alkynyl.
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Page/Page column 109
(2010/02/12)
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- Development of Irreversible Diphenyl Phosphonate Inhibitors for Urokinase Plasminogen Activator
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In this letter we report the synthesis and biochemical evaluation of selective, irreversible diphenyl phosphonate inhibitors for urokinase plasminogen activator (uPA). A diphenyl phosphonate group was introduced on the substratelike peptide Z-D-Ser-Ala-Arg, and modification of the guanidine side chain was investigated. A guanylated benzyl group appeared the most promising side chain modification. A kapp value in the 103 M -1 s-1 range for uPA was obtained, together with a selectivity index higher than 240 toward other trypsin-like proteases such as tPA, thrombin, plasmin, and FXa.
- Joossens,Van Der Veken,Lambeir,Augustyns,Haemers
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p. 2411 - 2413
(2007/10/03)
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- Cryptophycin compounds
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The present invention provides cryptophycin compounds of Formula I that are useful in the treatment of neoplasms.
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Page/Page column 151
(2010/02/05)
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