- 4-Acyl Pyrrole Capped HDAC Inhibitors: A New Scaffold for Hybrid Inhibitors of BET Proteins and Histone Deacetylases as Antileukemia Drug Leads
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Multitarget drugs are an emerging alternative to combination therapies. In three iterative cycles of design, synthesis, and biological evaluation, we developed a novel type of potent hybrid inhibitors of bromodomain, and extra-terminal (BET) proteins and histone deacetylases (HDACs) based on the BET inhibitor XD14 and well-established HDAC inhibitors. The most promising new hybrids, 49 and 61, displayed submicromolar inhibitory activity against HDAC1-3 and 6, and BRD4(1), and possess potent antileukemia activity. 49 induced apoptosis more effectively than the combination of ricolinostat and birabresib (1:1). The most balanced dual inhibitor, 61, induced significantly more apoptosis than the related control compounds 62 (no BRD4(1) affinity) and 63 (no HDAC inhibition) as well as the 1:1 combination of both. Additionally, 61 was well tolerated in an in vivo zebrafish toxicity model. Overall, our data suggest an advantage of dual HDAC/BET inhibitors over the combination of two single targeted compounds.
- Ahlert, Heinz,Bhatia, Sanil,Borkhardt, Arndt,Breit, Bernhard,Gunther, Stefan,Hansen, Finn K.,Hugle, Martin,Kraft, Fabian B.,Mishra, Pankaj,Schaker-Hubner, Linda,Schliehe-Diecks, Julian,Scholer, Andrea,Warstat, Robin
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p. 14620 - 14646
(2021/10/20)
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- (PYRIDIN-2-YL)AMINE DERIVATIVES AS TGF-BETA R1 (ALK5) INHIBITORS FOR THE TREATMENT OF CANCER
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The present invention relates to pharmaceutical compounds, compositions and methods, especially as they are related to compositions and methods for the treatment and/or prevention of a proliferation disorder associated with ΤGFβR1 activity, such as a cancer or fibrosis. The invention provides compounds of Formula (I) and Formula (II) as further described herein having an acidic moiety that enhances tissue specificity for targeted tissues and organs. The invention includes pharmaceutical compositions, pharmaceutical combinations, and methods of use of these compounds for treating conditions including cancer or fibrosis.
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Paragraph 00287-00288
(2020/07/15)
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- FUNCTIONALIZED NANOLUC INHIBITORS
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Compounds that may inhibit Oplophorus-derived luciferases are disclosed as well as compositions and kits comprising the compounds, and methods of using the compounds.
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Paragraph 00242-00244
(2018/07/29)
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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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- 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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- EP2 RECEPTOR AGONISTS
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A compound of Formula (I) or a salt, solvate and chemically protected form thereof, wherein: R5 is an optionally substituted C5-20 aryl or C4-20 alkyl group; A is selected from the group consisting of Formulae (Ai), (Aii), (Aiii) D is selected from Formulae (Di), (Dii), (Diii), (Div), (Dv) B is selected from the group consisting of Formulae (Bi), (Bii), (Biii), (Biv) (Bv).
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Page/Page column 64; 116-117
(2008/06/13)
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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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- THIAZOLE DERIVATIVES AND USE THEREOF
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The present invention is related to thiazole derivatives of Formula (I) in particular for the treatment and/or prophylaxis of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, transplantation, graft rejection or lung injuries.
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Page/Page column 173
(2008/06/13)
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- DRUG DISCHARGE PUMP INHIBITORS
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A medicament for preventive and/or therapeutic treatment of a microbial infection having an activity of eliminating resistance of a microorganism with acquired resistance to an antimicrobial agent, which comprises as an active ingredient a compound represented by the following general formula (I), a physiologically acceptable salt thereof, or a hydrate thereof: wherein R1 and R2 independently represent hydrogen atom, a halogen atom, carboxyl group and the like; J1 represents a 5- or 6-membered heteroaromatic ring; W1 represents -CH=CH-, -C≡C-, -CH2CH2- and the like; A1 represents phenylene group, pyridinediyl group, furandiyl group and the like; G1 represents oxygen atom, carbonyl group, ethynyl group and the like; p represents an integer of from 0 to 3; G2 represents phenylene group, furandiyl group, tetrahydrofurandiyl group and the like; G3 represents -CH2- or single bond; m and n represent an integer of 0 or 1; and Q1 represents an acidic group.
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- Synthesis and biological activity of new 3-hydroxy-3-methylglutaryl-CoA synthase inhibitors: 3-Oxetanones with a side chain mimicking the extended structure of 1233A
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Structural analogs of 1233A, a microbial metabolite inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase, were designed and synthesized. The 2-oxetanone moiety was left intact. All analogs prepared were tested for inhibition of HMG-CoA synt
- Hashizume,Ito,Morikawa,Kanaya,Nagashima,Usui,Tomoda,Sunazuka,Kumagai,Omura
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p. 2097 - 2107
(2007/10/02)
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- An azido-functionalized isocarbacyclin analogue acting as an efficient photoaffinity probe for a prostacyclin receptor
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A stable prostacyclin analogue, (15S)-18c, having an azidophenyl group as a photoaffinity labeling functionality has been synthesized. This compound has a sufficiently high affinity to the prostacyclin receptor protein in mastocytoma P-815 cells, exhibiting an IC50 value of 3 nM for the replacement of iloprost bound to the receptor protein. A photoaffinity probe compound, [3H]-(15S)-18c, is obtainable by reduction of the ketone 16c with [3H]NaBH4 - CeCl3 followed by alkaline hydrolysis of the methyl ester.
- Suzuki, Masaaki,Koyano, Hiroshi,Noyori, Ryoji,Hashimoto, Hitoshi,Negishi, Manabu,Ichikawa, Atsushi,Ito, Seiji
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p. 2635 - 2658
(2007/10/02)
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