- NURR1 RECEPTOR MODULATORS
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Described herein, inter alia, are Nurr1 receptor modulators and uses thereof. In an aspect is provided a method for treating a disease associated with dysregulation and/or degeneration of dopaminergic neurons in the central nervous system of a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein.
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Paragraph 0646; 1586-1588
(2020/09/08)
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- Discovery of a New Isoxazole-3-hydroxamate-Based Histone Deacetylase 6 Inhibitor SS-208 with Antitumor Activity in Syngeneic Melanoma Mouse Models
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Isoxazole is a five-membered heterocycle that is widely used in drug discovery endeavors. Here, we report the design, synthesis, and structural and biological characterization of SS-208, a novel HDAC6-selective inhibitor containing the isoxazole-3-hydroxamate moiety as a zinc-binding group as well as a hydrophobic linker. A crystal structure of the Danio rerio HDAC6/SS-208 complex reveals a bidentate coordination of the active-site zinc ion that differs from the preferred monodentate coordination observed for HDAC6 complexes with phenylhydroxamate-based inhibitors. While SS-208 has minimal effects on the viability of murine SM1 melanoma cells in vitro, it significantly reduced in vivo tumor growth in a murine SM1 syngeneic melanoma mouse model. These findings suggest that the antitumor activity of SS-208 is mainly mediated by immune-related antitumor activity as evidenced by the increased infiltration of CD8+ and NK+ T cells and the enhanced ratio of M1 and M2 macrophages in the tumor microenvironment.
- Shen, Sida,Hadley, Melissa,Ustinova, Kseniya,Pavlicek, Jiri,Knox, Tessa,Noonepalle, Satish,Tavares, Mauricio T.,Zimprich, Chad A.,Zhang, Guiping,Robers, Matthew B.,Ba?inka, Cyril,Kozikowski, Alan P.,Villagra, Alejandro
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p. 8557 - 8577
(2019/10/02)
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- 4“-O-Alkylated α-Galactosylceramide Analogues as iNKT-Cell Antigens: Synthetic, Biological, and Structural Studies
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Invariant natural killer T-cells (iNKT) are a glycolipid-responsive subset of T-lymphocytes that fulfill a pivotal role in the immune system. The archetypical synthetic glycolipid, α-galactosylceramide (α-GalCer), whose molecular framework is inspired by
- Janssens, Jonas,Bitra, Aruna,Wang, Jing,Decruy, Tine,Venken, Koen,van der Eycken, Johan,Elewaut, Dirk,Zajonc, Dirk M.,van Calenbergh, Serge
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p. 147 - 168
(2019/01/04)
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- PK/PD Disconnect Observed with a Reversible Endothelial Lipase Inhibitor
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Screening of a small set of nonselective lipase inhibitors against endothelial lipase (EL) identified a potent and reversible inhibitor, N-(3-(3,4-dichlorophenyl)propyl)-3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (5; EL IC50 = 6
- Hangeland, Jon J.,Abell, Lynn M.,Adam, Leonard P.,Jiang, Ji,Friends, Todd J.,Haque, Lauren E.,Neels, James,Onorato, Joelle M.,Chen, Alice Ye A.,Taylor, David S.,Yin, Xiaohong,Harrity, Thomas W.,Basso, Michael D.,Yang, Richard,Sleph, Paul G.,Gordon, David A.,Huang, Christine S.,Wexler, Ruth R.,Finlay, Heather J.,Lawrence, R. Michael
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supporting information
p. 673 - 678
(2018/07/25)
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- SPHINGOSINE KINASE INHIBITOR AMIDOXIME PRODRUGS
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Sphingosine kinases are enzymes that catalyze the biosynthesis of sphingosine-1-phosphate. The invention provides prodrugs of compounds that are effective for inhibition of sphingosine kinase type 1, sphingosine kinase type 2, or both, according to formula (I) as described herein. Formula I compounds are useful in the treatment of a range of diseases wherein increasing the level of sphingosine-1-phosphate in blood is medically indicated. The invention also provides pharmaceutical compositions of Formula I compounds.
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Page/Page column 133; 159
(2017/11/03)
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- SPHINGOSINE KINASE INHIBITORS
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Sphingosine kinases are enzymes that catalyze the biosynthesis of sphingosine-1-phosphate. The invention provides compounds that are effective for inhibition of sphingosine kinase type 1, sphingosine kinase type 2, or both. Certain compounds are selective for sphingosine kinase type 2 relative to sphingosine kinase type 1. Compounds of the invention can be used in treatment of a range of diseases wherein increasing the level of sphingosine-1-phosphate in blood is medically indicated. Diseases that can be treated by administration of an effective dose of a compound of the invention include a neoplastic disease that involves excess vascular growth; macular degeneration or diabetic retinopathy; an allergic disease such as asthma, an inflammatory disease of the eye such as uveitis, scleritis, or vitritis; an inflammatory disease of the kidney; a fibrotic disease; atherosclerosis; or pulmonary arterial hypertension. A compound of the invention can be used to improve the integrity of a vascular barrier in a disease where the vascular barrier is disrupted, such as cancer or Alzheimer's disease.
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Page/Page column 136
(2016/04/26)
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- N-(MONOCYCLIC ARYL),N'-PYRAZOLYL-UREA, THIOUREA, GUANIDINE AND CYANOGUANIDINE COMPOUNDS AS TRKA KINASE INHIBITORS
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Compounds of Formula (I) or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein Ring A, Ring C and X are as defined herein, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome.
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Paragraph 00523
(2014/06/11)
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- PYRIDINEDIONE CARBOXAMIDE INHIBITORS OF ENDOTHELIAL LIPASE
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The present invention provides compounds of Formula (I) as defined in the specification and compositions comprising any of such novel compounds. These compounds are endothelial lipase inhibitors which may be used as medicaments.
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Paragraph 00170
(2013/04/13)
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- PYRROLINONE CARBOXAMIDE COMPOUNDS USEFUL AS ENDOTHELIAL LIPASE INHIBITORS
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The present invention provides compounds of Formula (I): as defined in the specification and compositions comprising any of such novel compounds. These compounds are endothelial lipase inhibitors which may be used as medicaments. The disclosure also provi
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Paragraph 00183
(2013/04/13)
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- PYRROLINONE CARBOXAMIDE COMPOUNDS USEFUL AS ENDOTHELIAL LIPASE INHIBITORS
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The present invention provides compounds of Formula (I) or Formula (III): [INSERT CHEMICAL STRUCTURE HERE] (I) [INSERT CHEMICAL STRUCTURE HERE] (III) as defined in the specification and compositions comprising any of such novel compounds. These compounds
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Paragraph 00196
(2013/04/13)
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- CARBOXYLIC ACID COMPOUND
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To find a therapeutic agent and/or a preventive agent for diabetes mellitus or the like having excellent activity and safety. A compound represented by the following general formula (I), or a pharmacologically acceptable salt thereof. In the formula, X re
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Page/Page column 23
(2011/04/14)
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- NOVEL DXR INHIBITORS FOR ANTIMICROBIAL THERAPY
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The present invention generally concerns particular methods and compositions for antimicrobial therapy. In particuarl embodiments, the compositions target DXR. In specific embodiments, the compositions are electron-deficient heterocyclic rings.
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Page/Page column 88-89
(2011/05/05)
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- AMINE COMPOUND AND PHARMACEUTICAL USE THEREOF
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Provided is a novel amine compound represented by the following formula (I) having a superior peripheral blood lymphocyte decreasing action and superior in the immunosuppressive action, rejection suppressive action and the like, which shows decreased side effects of, for example, bradycardia and the like, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, or a solvate thereof. wherein each symbol is as defined in the specification.
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Page/Page column 89
(2010/04/25)
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