- COMPOUNDS, COMPOSITIONS AND METHODS FOR STABILIZING TRANSTHYRETIN AND INHIBITING TRANSTHYRETIN MISFOLDING
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Provided herein are compounds having activity against TTR related conditions, and pharmaceutically accepted salts and solvates thereof. Also provided are methods of using the compounds for inhibiting and preventing TTR aggregation and/or amyloid formation in the peripheral nerves, kidney, cardiac tissue, eye and CNS, and of treating a subject with peripheral TTR amyloidosis.
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Paragraph 0871-0874
(2021/08/06)
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- NEW CLASS OF DNA GYRASE AND/OR TOPOISOMERASE IV INHIBITORS WITH ACTIVITY AGAINST GRAM-POSITIVE AND GRAM-NEGATIVE BACTERIA
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The present invention relates to compounds having a structure of general formula (I), processes for their preparation, pharmaceutical compositions containing them as the active ingredient, to their use as medicaments and to their use in the manufacture of medicaments for use in the treatment of bacterial infections in humans and warm-blooded animals.
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Page/Page column 62
(2020/03/29)
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- Synthesis and Evaluation of N-Phenylpyrrolamides as DNA Gyrase B Inhibitors
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ATP-competitive inhibitors of DNA gyrase and topoisomerase IV are among the most interesting classes of antibacterial drugs that are unrepresented in the antibacterial pipeline. We developed 32 new N-phenylpyrrolamides and evaluated them against DNA gyrase and topoisomerase IV from E. coli and Staphylococcus aureus. Antibacterial activities were studied against Gram-positive and Gram-negative bacterial strains. The most potent compound displayed an IC50 of 47 nm against E. coli DNA gyrase, and a minimum inhibitory concentration (MIC) of 12.5 μm against the Gram-positive Enterococcus faecalis. Some compounds displayed good antibacterial activities against an efflux-pump-deficient E. coli strain (MIC=6.25 μm) and against wild-type E. coli in the presence of efflux pump inhibitor PAβN (MIC=3.13 μm). Here we describe new findings regarding the structure–activity relationships of N-phenylpyrrolamide DNA gyrase B inhibitors and investigate the factors that are important for the antibacterial activity of this class of compounds.
- Durcik, Martina,Tammela, P?ivi,Baran?oková, Michaela,Toma?i?, Tihomir,Ila?, Janez,Kikelj, Danijel,Zidar, Nace
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supporting information
p. 186 - 198
(2018/02/06)
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- Estrogen receptor coregulator binding modulators (ERXs) effectively target estrogen receptor positive human breast cancers
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The majority of human breast cancer is estrogen receptor alpha (ER) positive. While anti-estrogens/aromatase inhibitors are initially effective, resistance to these drugs commonly develops. Therapy-resistant tumors often retain ER signaling, via interaction with critical oncogenic coregulator proteins. To address these mechanisms of resistance, we have developed a novel ER coregulator binding modulator, ERX-11. ERX-11 interacts directly wiTheR and blocks the interaction between a subset of coregulators with both native and mutant forms of ER. ERX-11 effectively blocks ER-mediated oncogenic signaling and has potent anti-proliferative activity against therapy-sensitive and therapy-resistant human breast cancer cells. ERX-11 is orally bioavailable, with no overt signs of toxicity and potent activity in both murine xenograft and patient-derived breast tumor explant models. This first-in-class agent, with its novel mechanism of action of disrupting critical protein-protein interactions, overcomes the limitations of current therapies and may be clinically translatable for patients with therapy-sensitive and therapy-resistant breast cancers.
- Raj, Ganesh V.,Sareddy, Gangadhara Reddy,Ma, Shihong,Lee, Tae-Kyung,Viswanadhapalli, Suryavathi,Li, Rui,Liu, Xihui,Murakami, Shino,Chen, Chien-Cheng,Lee, Wan-Ru,Mann, Monica,Krishnan, Samaya Rajeshwari,Manandhar, Bikash,Gonugunta, Vijay K.,Strand, Douglas,Tekmal, Rajeshwar Rao,Ahn, Jung-Mo,Vadlamudi, Ratna K.
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supporting information
(2017/09/18)
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- GLP-1 receptor agonist compounds having stabilized regions
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The disclosure provides GLP-1 receptor agonist compounds having stabilized regions corresponding to alpha-helical regions of the natural peptide compounds. The disclosure also provides benzamide-containing exendin-4 analogs and alkene-constrained exendin-4 analogs, both of which have stabilized regions corresponding to alpha-helical regions of exendin-4.
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Page/Page column 42
(2016/01/09)
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- BRD4 Structure-Activity Relationships of Dual PLK1 Kinase/BRD4 Bromodomain Inhibitor BI-2536
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A focused library of analogues of the dual PLK1 kinase/BRD4 bromodomain inhibitor BI-2536 was prepared and then analyzed for BRD4 and PLK1 inhibitory activities. Particularly, replacement of the cyclopentyl group with a 3-bromobenzyl moiety afforded the most potent BRD4 inhibitor of the series (39j) with a Ki = 8.7 nM, which was equipotent against PLK1. The superior affinity of 39j over the parental compound to BRD4 possibly derives from improved interactions with the WPF shelf. Meanwhile, substitution of the pyrimidine NH with an oxygen atom reversed the PLK1/BRD4 selectivity to convert BI-2536 into a BRD4-selective inhibitor, likely owing to the loss of a critical hydrogen bond in PLK1. We believe further fine-tuning will furnish a BRD4 "magic bullet" or an even more potent PLK1/BRD4 dual inhibitor toward the expansion and improved efficacy of the chemotherapy arsenal.
- Chen, Lijia,Yap, Jeremy L.,Yoshioka, Makoto,Lanning, Maryanna E.,Fountain, Rachel N.,Raje, Mithun,Scheenstra, Jacob A.,Strovel, Jeffrey W.,Fletcher, Steven
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supporting information
p. 764 - 769
(2015/08/06)
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- Transition metals in organic synthesis. Part 101: Convergent total synthesis of 1,6-dioxygenated carbazole alkaloids
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Using a palladium(II)-catalysed oxidative cyclisation as key step, we describe a highly efficient total synthesis of a series of naturally occurring 1,6-dioxygenated carbazole alkaloids: clausenine, 6-methoxymurrayanine, clausenol, clausine G, clausine I, clausine Z and methyl 1,6-dihydroxy-9H- carbazole-3-carboxylate.
- B?rger, Carsten,Kn?lker, Hans-Joachim
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experimental part
p. 6727 - 6736
(2012/09/05)
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- Conformational properties of O-alkylated benzamides
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In this article, we report the synthesis, solid-state and solution-state conformational studies of O-alkylated aromatic benzamides based on two scaffolds. Intramolecular hydrogen bonding provides conformational pre-organization and side chains can interact with each other within a molecule. In the solid-state three-dimensional arrangement, the molecules further interact with each other through non-covalent interactions. Given, the demonstrated potential of this class of scaffolds to act as helix mimetics for the inhibition of protein-protein interactions (PPIs), these results provide key insight for future inhibitor design.
- Prabhakaran, Panchami,Azzarito, Valeria,Jacobs, Tia,Hardie, Michaele J.,Kilner, Colin A.,Edwards, Thomas A.,Warriner, Stuart L.,Wilson, Andrew J.
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supporting information; experimental part
p. 4485 - 4491
(2012/07/27)
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- 2-O-Alkylated para-benzamide α-helix mimetics: The role of scaffold curvature
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The design and synthesis of a new 2-O-alklyated benzamide α-helix mimetic is described. Comparison with regioisomeric 3-O-alkylated benzamides permits a preliminary evaluation of the role that mimetic curvature has in determining molecular recognition properties.
- Azzarito, Valeria,Prabhakaran, Panchami,Bartlett, Alice I.,Murphy, Natasha S.,Hardie, Michaele J.,Kilner, Colin A.,Edwards, Thomas A.,Warriner, Stuart L.,Wilson, Andrew J.
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supporting information; experimental part
p. 6469 - 6472
(2012/09/08)
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- Synthesis of functionalised aromatic oligamide rods
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A current goal in synthetic chemistry is the design and synthesis of molecules that adopt well defined conformations - so called foldamers. In this manuscript we describe a modular approach for construction of rod shaped para-oligobenzamide molecules. Our approach permits regiospecific incorporation of side chains through a phenolic ether linkage on the scaffold; a feature that partly restricts the conformation of the rod through intramolecular hydrogen-bonding. The Royal Society of Chemistry 2008.
- Plante, Jeffrey,Campbell, Fred,Malkova, Barbora,Kilner, Colin,Warriner, Stuart L.,Wilson, Andrew J.
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p. 138 - 146
(2008/09/20)
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- Transition metals in organic synthesis, Part 85.1 A general approach to 1,6-dioxygenated carbazole alkaloids - first total synthesis of clausine G, clausine I, and clausine Z
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Using the palladium-catalyzed construction of the carbazole framework, a highly efficient route to 1,6-dioxygenated carbazole alkaloids has been developed and applied to the total synthesis of clausenine, 6- methoxymurrayanine, clausenol, clausine G, clausine I, and clausine Z. The three latter natural products have been synthesized for the first time. Thieme Stuttgart.
- B?rger, Carsten,Kn?lker, Hans-Joachim
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body text
p. 1698 - 1702
(2009/05/07)
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- NOVEL HYDROXYETHYLAMINE AND KETONE COMPOUNDS HAVING ASP2 INHIBITORY ACTIVITY
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The present invention relates to novel hydroxyethylamine and ketone compounds having Asp2 (β-secretase, BACE1 or Memapsin-2) inhibitory activity, processes for their preparation, to compositions containing them and to their use in the treatment of disease
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Page/Page column 23
(2008/06/13)
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- Synthesis of indoles: Efficient functionalisation of the 7-position
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Traditional strategies in indole chemistry do not allow high-yielding access to some substitution patterns such as 3,5,7-trisubstituted indoles. We report in this article the efficient synthesis of this type of indole. The Heck cyclisation strategy we use
- Charrier, Nicolas,Demont, Emmanuel,Dunsdon, Rachel,Maile, Graham,Naylor, Alan,O'Brien, Alistair,Redshaw, Sally,Theobald, Pam,Vesey, David,Walter, Daryl
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p. 3467 - 3477
(2008/02/10)
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- Synthesis of 3,5,7-substituted indoles via heck cyclisation
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Traditional strategies in indole chemistry do not allow high yielding access to some substitution patterns such as 3,5,7-trisubstituted indoles. We report in this article the efficient synthesis of this type of indole. The Heck cyclisation strategy we use
- Charrier, Nicolas,Demont, Emmanuel,Dunsdon, Rachel,Maile, Graham,Naylor, Alan,O'Brien, Alistair,Redshaw, Sally,Theobald, Pam,Vesey, David,Walter, Daryl
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p. 3071 - 3074
(2007/10/03)
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- Arylsulfonamide ethers, and methods of use thereof
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Novel arylsulfonamide ether compounds and pharmaceutical compositions thereof are described. The use of the novel arylsulfonamide ether compounds and pharmaceutical compositions thereof as inhibitors of interleukin-1β converting enzyme and other cysteine proteases in the ICE family is also decribed. In addition, methods of treating stroke, inflammatory diseases, septic shock, repurfusion injury, Alzheimer's disease, and shigellosis using a compound of the invention or a pharmaceutical composition thereof are described.
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