- POLYAROMATIC UREA DERIVATIVES AND THEIR USE IN THE TREATMENT OF MUSCLE DISEASES
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The current invention provides urea derivatives, in particular compounds having the core structure heteroaryl-NH-CO-NH-aryl-O- heteroaryl, for use in treating, ameliorating, delaying, curing and/ or preventing a disease or condition associated with muscle cells and/or satellite cells, such as Duchenne muscular dystrophy, Becker muscular dystrophy, cachexia or sarcopenia.
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Page/Page column 166
(2021/01/29)
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- Discovery of 1-(1H-indazol-4-yl)-3-((1-phenyl-1H-pyrazol-5-yl)methyl) ureas as potent and thermoneutral TRPV1 antagonists
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A series of 1-indazol-3-(1-phenylpyrazol-5-yl)methyl ureas were investigated as hTRPV1 antagonists. The structure–activity relationship study was conducted systematically for both the indazole A-region and the 3-trifluoromethyl/t-butyl pyrazole C-region to optimize the antagonism toward the activation by capsaicin. Among them, the antagonists 26, 50 and 51 displayed highly potent antagonism with Ki(CAP) = 0.4–0.5 nM. Further, in vivo studies in mice indicated that these derivatives both antagonized capsaicin induced hypothermia, consistent with their in vitro activity, and themselves did not induce hyperthermia. In the formalin model, 51 showed anti-nociceptive activity in a dose-dependent manner.
- Kang, Jin Mi,Kwon, Sun Ok,Ann, Jihyae,Blumberg, Peter M.,Ha, Heejin,Yoo, Young Dong,Frank-Foltyn, Robert,Lesch, Bernhard,Bahrenberg, Gregor,Stockhausen, Hannelore,Christoph, Thomas,Lee, Jeewoo
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- Pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists
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A series of 1-substituted 3-(t-butyl/trifluoromethyl)pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The structure activity relationship indicated that the 3-chlorophenyl group at the 1-position of pyrazole was the optimized hydrophobic group for antagonistic potency and the activity was stereospecific to the S-configuration, providing exceptionally potent antagonists 13S and 16S with Ki(CAP) = 0.1 nM. Particularly significant, 13S exhibited antagonism selective for capsaicin and NADA and not for low pH or elevated temperature. Both compounds also proved to be very potent antagonists for rTRPV1, blocking in vivo the hypothermic action of capsaicin, consistent with their in vitro mechanism. The docking study of compounds 13S and 16S in our hTRPV1 homology model indicated that the binding modes differed somewhat, with that of 13S more closely resembling that of GRT12360.
- Lee, Sunho,Kim, Changhoon,Ann, Jihyae,Thorat, Shivaji A.,Kim, Eunhye,Park, Jongmi,Choi, Sun,Blumberg, Peter M.,Frank-Foltyn, Robert,Bahrenberg, Gregor,Stockhausen, Hannelore,Christoph, Thomas,Lee, Jeewoo
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p. 4383 - 4388
(2017/09/12)
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- Synthesis and p38 inhibitory activity of some novel substituted N,N′-diarylurea derivatives
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We have identified a novel series of substituted N,N′-diarylurea p38α inhibitors. The inhibitory activity of the target compounds against the enzyme p38α, MAPKAPK2 in BHK cells, TNF-α release in LPS-stimulated THP-1 cells and p38α binding experiments were
- Zhu, Dianxi,Xing, Qifeng,Cao, Ruiyuan,Zhao, Dongmei,Zhong, Wu
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- Biophysical investigation and conformational analysis of p38α kinase inhibitor doramapimod and its analogues
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Doramapimod (BIRB 796) is a potent inhibitor of p38α mitogen-activated protein kinase. It contains an aryl-pyrazole scaffold as a pharmacophore critical for binding. The aryl-pyrazole scaffold is not planar and adopts an out-of-plane conformation, which is described by the torsion angle θ. In this letter, we report the chemical synthesis and biophysical characterization of different analogues of doramapimod (3-12) exhibiting distinctly different aryl-pyrazole torsion angle θ values. The torsion angle θ values of the synthesized analogues (3-6) were determined by crystal structural analysis and the binding affinities to p38α kinase investigated by microscale thermophoresis. Our results unveil a clear correlation between kinase binding and the torsion angle θ of tested doramapimod analogues, highlighting the importance of inhibitor conformation for protein binding.
- Nasiri, Amir H.,Saxena, Krishna,Bats, Jan W.,Nasiri, Hamid R.,Schwalbe, Harald
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p. 1421 - 1428
(2016/07/21)
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- Synthesis and Biological Evaluation of Chromenylurea and Chromanylurea Derivatives as Anti-TNF-a agents that Target the p38 MAPK Pathway
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A series of 1-aryl-3-(2H-chromen-5-yl)urea and 1-aryl-3-(chroman-5-yl)urea derivatives were designed, synthesized and evaluated for their inhibitory activities towards TNF-a production in lipopolysaccharide-stimulated THP-1 cells. The most active compound, 40g, inhibited TNF-a release with an IC50 value of 0.033 μM, which is equipotent to that of BIRB796 (IC50 = 0.032 μM).
- Li, Xingzhou,Zhou, Xinming,Zhang, Jing,Wang, Lili,Long, Long,Zheng, Zhibing,Li, Song,Zhong, Wu
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p. 2004 - 2028
(2014/03/21)
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- KINASE INHIBITORS
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Compounds of formula (I) or a pharmaceutically acceptable salt thereof: wherein R2, W, A, Y and R1 are as defined in the specification, are p38 MAPK inhibitors, useful as anti-inflammatory agents in the treatment of, inter alia, diseases of the respiratory tract.
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Page/Page column 105-106
(2013/06/27)
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- KINASE INHIBITORS
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Compounds of formula (I): wherein R2, W, A, Y, and R1 are as defined in the specification, and pharmaceutically acceptable salts thereof, are p38 MAPK inhibitors, and are useful as anti-inflammatory agents in the treatment of, inter alia, diseases of the respiratory tract.
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Paragraph 0428; 0429
(2013/06/27)
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- Anti-inflammatory medicaments
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Novel compounds and methods of using those compounds for the treatment of inflammatory conditions are provided. In a preferred embodiment, modulation of the activation state of p38 kinase protein comprises the step of contacting the kinase protein with the novel compounds.
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- DISUBSTITUTED UREAS AS KINASE INHIBITORS
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The invention relates to compounds of the formula (I), their use as kinase inhibitors, new pharmaceutical formulations comprising said compounds, said compounds for use in the diagnostic or therapeutic treatment of warm-blooded animals, especially humans,
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Page/Page column 22
(2009/05/28)
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- MODULATION OF PROTEIN FUNCTIONALITIES
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New methods for the rational identification of molecules capable of interacting with specific naturally occurring proteins are provided, in order to yield new pharmacologically important compounds and treatment modalities. Broadly, the method comprises the steps of identifying a switch control ligand forming a part of a particular protein of interest, and also identifying a complemental switch control pocket forming a part of the protein and which interacts with said switch control ligand. The ligand interacts in vivo with the pocket to regulate the conformation and biological activity of the protein such that the protein assumes a first conformation and a first biological activity upon the ligand-pocket interaction, and assumes a second, different conformation and biological activity in the absence of the ligand-pocket interaction. Next, respective samples of said protein in the first and second conformations are provided, and these are screened against one or more candidate molecules by contacting the molecules and the samples. Thereupon, small molecules which bind with the protein at the region of the pocket may be identified. Novel protein-modulator adducts and methods of altering protein activity are also provided.
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- INHIBITION OF RAF KINASE USING ARYL AND HETEROARYL SUBSTITUTED HETEROCYCLIC UREAS
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Methods of treating tumors mediated by raf kinase, with substituted urea compounds, and such compounds per se,
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Page/Page column 8
(2008/06/13)
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- UREA COMPOUNDS USEFUL IN THE TREATMENT OF CANCER
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Pyrazole urea compounds, pharmaceutical compositions which contain them and methods for treating cancer using them.
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Page/Page column 77-78
(2008/06/13)
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- HETEROBICYCLIC CARBOXAMIDES AS INHIBITORS FOR KINASES
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The invention relates to novel compounds of formula (I) and their use in the treatment of the animal or human body, to pharmaceutical compositions comprising a compound of formula (I) and to the use of a compound of formula (I) for the preparation of pharmaceutical compositions for use in the treatment of protein kinase dependent diseases, especially of proliferative diseases, such as in particular tumour diseases.
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Page/Page column 66
(2010/11/28)
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- INHIBITION OF p38 KINASE ACTIVITY USING ARYL AND HETEROARYL SUBSTITUTED HETEROCYCLIC UREAS
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This invention relates to the use of a group of aryl ureas in treating cytokine mediated diseases other than cancer and proteolytic enzyme mediated diseases other than cancer, and pharmaceutical compositions for use in such therapy.
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Page/Page column 14-15
(2010/11/24)
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- Triazolopyridinylsulfanyl derivatives as p38 MAP kinase inhibitors
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A compound of formula (I), or a pharmaceutically acceptable salt and/or solvate (including hydrate) thereof; and the use of a compound of formula (I) in the treatment of a TNF-mediated disease, disorder, or condition, or a p38-mediated disease, disorder, or condition, in particular the allergic and non-allergic airways diseases, more particularly obstructive or inflammatory airways diseases, preferably chronic obstructive pulmonary disease.
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Page/Page column 31; 34
(2008/06/13)
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- ENZYME MODULATORS AND TREATMENTS
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Novel compounds and methods of using those compounds for the treatment of inflammatory conditions, hyperproliferative diseases, cancer, and diseases characterized by hypervascularization are provided. In a preferred embodiment, modulation of the activation state of p38 kinase protein ab1 kinase protein, bcr-ab1 kinase protein, braf kinase protein, VEGFR kinase protein, or PDGFR kinase protein comprises the step of contacting said kinase protein with the novel compounds.
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Page/Page column 348
(2008/06/13)
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- INHIBITION OF RAF KINASE USING ARYL AND HETEROARYL SUBSTITUTED HETEROCYCLIC UREAS
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Methods of treating tumors mediated by raf kinase, with substituted urea compounds, and such compounds per se.
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Page/Page column 13
(2010/11/08)
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- Anti-inflammatory medicaments
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Novel compounds and methods of using those compounds for the treatment of inflammatory conditions are provided. In a preferred embodiment, modulation of the activation state of p38 kinase protein comprises the step of contacting the kinase protein with the novel compounds.
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- 1-Phenyl-5-pyrazolyl ureas: Potent and selective p38 kinase inhibitors
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Inhibitors of the MAP kinase p38 are potentially useful for the treatment of arthritis and osteoporosis. Several 2,3-dichlorophenyl ureas were identified as small-molecule inhibitors of p38 by a combinatorial chemistry effort. Optimization for cellular potency led to the discovery of a new class of potent and selective p38 kinase inhibitors, exemplified by the 1-phenyl-5-pyrazolyl urea 7 (IC50 = 13 nM). (C) 2000 Elsevier Science Ltd.
- Dumas, Jacques,Hatoum-Mokdad, Holia,Sibley, Robert,Riedl, Bernd,Scott, William J.,Monahan, Mary Katherine,Lowinger, Timothy B.,Brennan, Catherine,Natero, Reina,Turner, Tiffany,Johnson, Jeffrey S.,Schoenleber, Robert,Bhargava, Ajay,Wilhelm, Scott M.,Housley, Timothy J.,Ranges, Gerald E.,Shrikhande, Alka
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p. 2051 - 2054
(2007/10/03)
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