- MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE
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The present disclosure relates to bifunctional compounds, which find utility as modulators of Kirsten rat sarcoma protein (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation, accumulation, and/or overactivation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 00807-00808
(2019/10/29)
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- CERAMIDE GALACTOSYLTRANSFERASE INHIBITORS FOR THE TREATMENT OF DISEASE
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Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with the enzyme ceramide galactosyltransferase (CGT), such as, for example, lysosomal storage diseases. Examples of lysosomal storage diseases include, for example, Krabbe disease and Metachromatic Leukodystrophy.
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Paragraph 00204; 00205; 00337; 00338
(2018/07/29)
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- Fragment-Based Design, Synthesis, and Biological Evaluation of 1-Substituted-indole-2-carboxylic Acids as Selective Mcl-1 Inhibitors
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Based on a known selective Mcl-1 inhibitor, 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylic acid, we applied a fragment-based approach to obtain new molecules that extended into the p1 pocket of the BH3 groove and then exhibited binding selectivity for the Mcl-1 over the Bcl-2 protein. After we deconstructed the 1H-indole-2-carboxylic acid from the parental molecule, a benzenesulfonyl was substituted at the 1-position to adopt a geometry preferred for accessing the p1 pocket according to the binding mode of the parental molecule identified by X-ray crystallography. A linear relationship between the free energy of ligand binding (ΔG) and the count of non-hydrogen heavy atoms (HAC) was maintained during the molecular growing to occupy the p1 pocket. Finally, we not only obtained compound 12 with a 7.5-fold selectivity to Mcl-1 (Ki = 0.48 μM by fluorescence polarization) over Bcl-2 (Ki = 3.6 μM), but also provided evidence that additional occupation of the p1 pocket is more favorable for Mcl-1 than for Bcl-2 binding, and contributes more to Mcl-1 inhibition than occupation of the p2 pocket. Compound 12 exhibited a selective killing ability on Mcl-1-dependent cancer cells.
- Wang, Ziqian,Xu, Wenjie,Song, Ting,Guo, Zongwei,Liu, Lu,Fan, Yudan,Wang, Anhui,Zhang, Zhichao
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- NOVEL BENZENESULFONAMIDE COMPOUNDS, METHOD FOR SYNTHESIZING SAME, AND USE THEREOF IN MEDICINE AS WELL AS IN COSMETICS
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Provided herein are novel benzenesulfonamide compounds having a structure of formula (I) below: as well as to the method for synthesizing same and to the use thereof in pharmaceutical compositions to be used in human or veterinary medicine, as well as to
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Paragraph 0217
(2014/09/30)
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- COMPOUNDS AND METHODS FOR INHIBITING NHE-MEDIATED ANTIPORT IN THE TREATMENT OF DISORDERS ASSOCIATED WITH FLUID RETENTION OR SALT OVERLOAD AND GASTROINTESTINAL TRACT DISORDERS
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The present disclosure is directed to compounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease,
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Page/Page column 107; 108
(2014/03/25)
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- Arylsulfonamide inhibitors of aggrecanases as potential therapeutic agents for osteoarthritis: Synthesis and biological evaluation
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Aggrecanases, in particular aggrecanase-2 (ADAMTS-5), are considered the principal proteases responsible for aggrecan degradation in osteoarthritis. For this reason, considerable effort has been put on the discovery and development of aggrecanase inhibito
- Nuti, Elisa,Santamaria, Salvatore,Casalini, Francesca,Yamamoto, Kazuhiro,Marinelli, Luciana,La Pietra, Valeria,Novellino, Ettore,Orlandini, Elisabetta,Nencetti, Susanna,Marini, Anna Maria,Salerno, Silvia,Taliani, Sabrina,Da Settimo, Federico,Nagase, Hideaki,Rossello, Armando
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p. 379 - 394
(2013/05/22)
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- NOVEL BENZENESULFONAMIDE COMPOUNDS, METHOD FOR SYNTHESIZING SAME, AND USE THEREOF IN MEDICINE AS WELL AS IN COSMETICS
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Benzenesulfonamide compounds having a structure of the following general formula (I) are described. Also described, are methods for synthesizing the compounds, and to the use thereof in pharmaceutical compositions for human or veterinary medicine and in c
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Page/Page column 12
(2012/05/20)
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- NOVEL BENZENESULFONAMIDE COMPOUNDS, METHOD FOR SYNTHESIZING SAME, AND USE THEREOF IN MEDICINE AS WELL AS IN COSMETICS
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Benzenesulfonamide compounds having a structure of formula (I) are described. Also described, are methods for synthesizing the compounds and to the use thereof in pharmaceutical compositions for human or veterinary medicine and in cosmetic compositions.
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Page/Page column 14
(2013/02/27)
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- Asymmetric transfer hydrogenation of ketones with a polyethylene glycol bound Ru catalyst in water
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A new polyethylene glycol supported Ru catalyst was synthesized and applied in the asymmetric transfer hydrogenation of various aromatic ketones in water with high chemical yields and enantioselectivities without adding any surfactants. The catalyst could be easily recycled several times without a significant loss of enantioselectivity and activity.
- Liu, Juntao,Zhou, Yougui,Wu, Yinuo,Li, Xingshu,Chan, Albert S.C.
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p. 832 - 837
(2008/09/20)
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- Synthesis of new carbon-11-labeled 7-aroylaminoindoline-1-sulfonamides as potential PET agents for imaging of tubulin polymerization in cancers
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The tubulin polymerization is an attractive target for anticancer therapy and in the development of cancer imaging agents for use in biomedical imaging technique positron emission tomography (PET). 7-Aroyl-aminoindoline-1 -sulfonamides are a novel class o
- Wang, Min,Gao, Mingzhang,Miller, Kathy D.,Sledge, George W.,Hutchins, Gary D.,Zheng, Qi-Huang
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- Design, synthesis and biological activity of azasugar-based CD163 ectodomain shedding inhibitors
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A series of metalloproteinase CD163 ectodomain shedding inhibitors based on azasugar hydroxamic acid scaffold has been synthesized. Among the synthesized compounds, the benzyl derivative 4a and the methyl derivative 4f exhibits 66 and 51 % inhibition, res
- Attia, Mohamed I.,Timmermann, Meike,Hoegger, Petra,Herdeis, Claus
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p. 3669 - 3675
(2008/03/14)
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- Preparation of polymer-supported Ru-TsDPEN catalysts and use for enantioselective synthesis of (S)-fluoxetine
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Polymer-supported chiral ligands 9 and 17 were prepared based on Noyori's (1S,2S)- or (1R,2R)-N-(p-tolylsulfonyl)-1,2-diphenylethylenediamine. The combination with [RuCl2(p-cymene)]2 has been shown to exhibit high activities and enantioselectivities for heterogeneous asymmetric transfer hydrogenation of aromatic ketones (19a-c) with formic acid-triethylamine azeotrope as the hydrogen donor, whereby affording the respective optically active alcohols 20a-c, the key precursors of chiral fluoxetine. As exemplified by ligand 17 for substrate 19c, the catalysts can be recovered and reused in three consecutive runs with no significant decline in enantioselectivity. The procedure avoids the plausible contamination of fluoxetine by the toxic transition metal species. The Royal Society of Chemistry 2005.
- Li, Yangzhou,Li, Zhiming,Li, Feng,Wang, Quanrui,Tao, Fanggang
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p. 2513 - 2518
(2007/10/03)
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- ORGANIC COMPOUNDS
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Compounds of the formula (I) provide pharmacological agents which bind to Peroxisome Proliferator-Activated Receptors (PPARs). Accordingly, the compounds of the present invention are useful for the treatment of conditions mediated by the PPAR receptor activity in mammals. Such conditions include dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, inflammatory bowel diseases (IBDs), ulcerative colitis and Crohn's disease. The compounds of the present invention are particularly useful in mammals as hypoglycemic agents for the treatment and prevention of conditions in which impaired glucose tolerance, hyperglycemia and insulin resistance are implicated, such as type-1 and type-2 diabetes, and Syndrome X.
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- Hydroxy pipecolate hydroxamic acid derivatives
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A compound of the formula wherein R1, R2R3, R4R5, R6, R7, R8, R9and Ar are as defined above, useful in the treatment of a condition selected from the group consisting of arthritis, cancer, and other diseases characterized by matrix metalloproteinase or mammalian reprolysin activity. In addition, the compounds of the present invention may be used in combination therapy with standard non-steroidal anti-inflammatory drugs (NSAID'S), COX-2 inhibitors and analgesics, and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and other alkaloids, such as vincristine, in the treatment of cancer.
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- Deep ultraviolet absorbent and its use in pattern formation
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A deep ultraviolet absorbent comprising at least one compound having one or more glycidyl groups in the molecule and at least one anthracene derivative, and a solvent capable of dissolving these compounds is effective for preventing reflection of deep ultraviolet light from a substrate during formation of resist pattern, resulting in forming ultra-fine patterns without causing notching and halation.
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- Amnesia-reversal activity of a series of 5-alkoxy-1-arylsulfonyl-2-pyrrolidinones
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A series of 5-alkoxy-1-arylsulfonyl-2-pyrrolidinones were prepared by condensation of arylsulfonyl chlorides with 5-alkoxy-2-pyrrolidinones.Most compounds reversed electroconvulsive shock-induced amnesia in mice, showing the typical inverted U-shaped dose
- Toja, E,Gorini, C,Zirotti, C,Barzaghi, F,Galliani, G
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p. 403 - 413
(2007/10/02)
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