- Selectivity, ligand deconstruction, and cellular activity analysis of a BPTF bromodomain inhibitor
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Bromodomain and PHD finger containing protein transcription factor (BPTF) is an epigenetic protein involved in chromatin remodelling and is a potential anticancer target. The BPTF bromodomain has one reported small molecule inhibitor (AU1, rac-1). Here, advances made on the structure-activity relationship of a BPTF bromodomain ligand are reported using a combination of experimental and molecular dynamics simulations leading to the active enatiomer (S)-1. Additionally, a ligand deconstruction analysis was conducted to characterize important pharmacophores for engaging the BPTF bromodomain. These studies have been enabled by a protein-based fluorine NMR approach, highlighting the versatility of the method for selectivity, ligand deconstruction, and ligand binding. To enable future analysis of biological activity, cell growth analyses in a panel of cancer cell lines were carried out using CRISPR-Cas9 and (S)-1 to identify cell-based model systems that are sensitive to BPTF inhibition.
- Kirberger, Steven E.,Ycas, Peter D.,Johnson, Jorden A.,Chen, Chen,Ciccone, Michael F.,Woo, Rinette W. L.,Urick, Andrew K.,Zahid, Huda,Shi, Ke,Aihara, Hideki,McAllister, Sean D.,Kashani-Sabet, Mohammed,Shi, Junwei,Dickson, Alex,Dos Santos, Camila O.,Pomerantz, William C. K.
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supporting information
p. 2020 - 2027
(2019/02/20)
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- AMINE-SUBSTITUTED ARYL OR HETEROARYL COMPOUNDS AS EHMT1 AND EHMT2 INHIBITORS
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The present disclosure relates to amine-substituted aryl or heteroaryl compounds. The present disclosure also relates to pharmaceutical compositions containing these compounds and methods of treating a disorder (e.g., sickle cell anemia) via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2, by administering an amine-substituted aryl or heteroaryl compound disclosed herein or a pharmaceutical composition thereof to subjects in need thereof. The present disclosure also relates to the use of such compounds for research or other non-therapeutic purposes.
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Paragraph 0448-0450
(2017/11/10)
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- USES OF SALT-INDUCIBLE KINASE (SIK) INHIBITORS
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The present disclosure provides methods of treating and/or preventing inflammatory bowel disease (IBD) and graft-versus-host disease (GVHD) using salt-inducible kinase (SIK) inhibitors, such as macrocyclic SIK inhibitors of Formula (I), imidazolyl SIK inh
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Paragraph 00412-00413
(2016/04/20)
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- Synthesis and functional characterization of imbutamine analogs as histamine H3 and H4 receptor ligands
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Imbutamine (4-(1H-imidazol-4-yl)butanamine) is a potent histamine H 3 (H3R) and H4 receptor (H4R) agonist (EC50 values: 3 and 66 nM, respectively). Aiming at improved selectivity for the H4R, the imidazole ring in imbutamine was methyl-substituted or replaced by various differently substituted heterocycles (1,2,3-triazoles, 1,2,4-triazoles, pyridines, pyrimidines) as potential bioisosteres. Investigations in [35S]GTPγS binding assays using membranes of Sf9 insect cells expressing the respective human histamine receptor subtype revealed only very weak activity of most of the synthesized hetarylalkylamines at both receptors. By contrast, the introduction of substituents at the 4-imidazolyl ring was most effective regarding H 4R selectivity. This holds for methyl substitution in position 2 and, especially, in position 5. 5-Methylimbutamine (H4R: EC50 = 59 nM, α = 0.8) was equipotent with imbutamine at the hH4R, but revealed about 16-fold selectivity for the hH4R compared to the hH3R (EC50 980 nM, α = 0.36), whereas imbutamine preferred the hH3R. The functional activities were in agreement with radioligand binding data. The results support the hypothesis that, by analogy with histamine, methyl substitution in histamine homologs offers a way to shift the selectivity in favor of the H4R. According to a bioisosteric approach, the imidazole ring in the dual histamine H3/H4 receptor agonist imbutamine (n = 4) was replaced by various five- and six-membered N-heterocycles. Whereas these structural modifications resulted in a reduction or loss of activity at both receptors, 5-methyl substitution at the imidazol-4-yl ring in imbutamine changed the receptor subtype selectivity in favor of the H4R.
- Geyer, Roland,Kaske, Melanie,Baumeister, Paul,Buschauer, Armin
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- 2-PHENYLAMINOPYRIMIDINE DERIVATIVES AS KINASE LRRK2 MODULATORS FOR THE TREATMENT OF PARKINSON'S DISEASE
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Specific Compounds of formula (I): or pharmaceutically acceptable salts thereof, wherein m, X, R, R2, R3, R, R6 and R7 are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with LRRK2 receptor, such as Parkinson's disease.
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Page/Page column 57
(2013/06/27)
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- AMINOPYRIMIDINE DERIVATIVES AS LRRK2 INHIBITORS
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Compounds of the formula I: or pharmaceutically acceptable salts thereof, wherein m, n. X, R1, R2, R3, R5, R6 and R7 are as defined herein. Also disclosed are methods of making the compound
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Page/Page column 22
(2011/12/14)
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- 2-ARYLBENZOTHIOPHENE DERIVATIVES OR PHARCEUTICALLY ACCEPTABLE SALTS THEREOF, PREPARATION METHOD THEREOF, AND PHARCEUTICAL COMPOSITION FOR THE DIAGNOSIS OR TREATMENT OF DEGENERATIVE BRAIN DISEASE CONTAINING THE SAME AS ACTIVE INGREDIENT
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2-arylbenzothiophene derivatives or pharmaceutically acceptable salts thereof, a preparation method thereof, and a pharmaceutical composition for the diagnosis or treatment of degenerative brain disease containing the same as an active ingredient. Since the 2-arylbenzothiophene derivatives of Formula 1 have a relatively high binding affinity for β-amyloid, they can be used as diagnostic reagents for diagnosing Alzheimer's disease at an early stage by non-invasive techniques when they are labeled with radioisotopes: wherein R1-R4, V, W, X, Y and Z are as defined in the Detailed Descript of the specification. Further, when the pharmaceutical composition containing the 2-arylbenzothiophene derivative binds with a low-molecular weight β-amyloid peptide binding compound, generation of malignant high-molecular weight β-amyloid deposits is minimized. Accordingly, the pharmaceutical composition can be used as a therapeutic agent of degenerative brain disease such as Alzheimer's disease.
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Page/Page column 30
(2010/11/03)
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- NOVEL SEH INHIBITORS AND THEIR USE
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The invention is directed to novel sEH inhibitors and their use in the treatment of diseases mediated by the sEH enzyme. Specifically, the invention is directed to compounds according to Formula (I): wherein R1, R2, R3, R5a, R6a, A, B, K, L, M, Y, Z, x, a
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Page/Page column 26-27
(2009/09/05)
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- N-substituted 2′-(aminoaryl)benzothiazoles as kinase inhibitors: Hit identification and scaffold hopping
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Starting with a hit from vHTS attained by a docking procedure of virtual compounds into ATP pockets of different kinases applying the 4SCan technology, variations of the adenine mimic resulted in the identification of promising scaffolds, giving rise to in vitro IC50 values in the nanomolar range on different kinases down to 63 nM.
- Tasler, Stefan,Mueller, Oliver,Wieber, Tanja,Herz, Thomas,Krauss, Rolf,Totzke, Frank,Kubbutat, Michael H.G.,Schaechtele, Christoph
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scheme or table
p. 1349 - 1356
(2009/11/30)
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- 2-arylbenzothiazole analogues and uses thereof
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The present invention relates to compounds of the general formula (I) and salts, prodrugs, and stereoisomers thereof, wherein Y independently represents S, O, NR2, SO, SO2; A independently represents a fife- or six-membered aromatic carbocycle or heterocycle and wherein R1 to R20 in formula (I) represent independently of each other a variety of different substituents comprising alkyl, aryl, aralkyl, alkylaryl, heteroaryl groups and monofunctional moieties.
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Page/Page column 15
(2008/06/13)
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- 2-Arylbenzothiazole analogues and uses thereof in the treatment of cancer
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The present invention relates to anticancer compounds of the general formula (I) and salts and physiologically functional derivatives thereof, wherein Y independently represents S, O, NR 2 , SO, SO 2 ; A independently represents a five- or six-membered aromatic carbocycle or heterocycle and wherein R 1 in formula (I) represents one of the heteroaryl groups defined in the claims.
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Page/Page column 26-27
(2010/11/25)
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- Development of N-2,4-pyrimidine-N-phenyl-N′-phenyl ureas as inhibitors of tumor necrosis factor alpha (TNF-α) synthesis. Part 1
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A new class of tumor necrosis factor alpha (TNF-α) synthesis inhibitors based on an N-2,4-pyrimidine-N-phenyl-N′-phenyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-α productio
- Brugel, Todd A.,Maier, Jennifer A.,Clark, Michael P.,Sabat, Mark,Golebiowski, Adam,Bookland, Roger G.,Laufersweiler, Matthew J.,Laughlin, Steven K.,VanRens, John C.,De, Biswanath,Hsieh, Lily C.,Mekel, Marlene J.,Janusz, Michael J.
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p. 3510 - 3513
(2007/10/03)
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- SUBSTITUTED ANTHRANILIC AMIDE DERIVATIVES AND METHODS OF USE
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Selected compounds are effective for prophylaxis and treatment of diseases, such as angiogenesis mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
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- 2,6-di,2,4,6-, 2,5,6-tri and 2,4,5,6-tetra-substituted pyrimidines, their pharmaceutically acceptable salts, pharmaceutical compositions containing same and their use in the treatment of neurological diseases
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2,6-di-, 2,4,6-, 2,5,6-tri- or 2,4,5,6-tetra-substituted pyrimidines, and 2,6-di-substituted pyridines. These compounds are useful for treatment of neurological diseases.
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