- Design, Synthesis, and in vitro Evaluation of P2X7 Antagonists
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The P2X7 receptor is a promising target for the treatment of various diseases due to its significant role in inflammation and immune cell signaling. This work describes the design, synthesis, and in vitro evaluation of a series of novel derivatives bearing diverse scaffolds as potent P2X7 antagonists. Our approach was based on structural modifications of reported (adamantan-1-yl)methylbenzamides able to inhibit the receptor activation. The adamantane moieties and the amide bond were replaced, and the replacements were evaluated by a ligand-based pharmacophore model. The antagonistic potency of the synthesized analogues was assessed by two-electrode voltage clamp experiments, using Xenopus laevis oocytes that express the human P2X7 receptor. SAR studies suggested that the replacement of the adamantane ring by an aryl-cyclohexyl moiety afforded the most potent antagonists against the activation of the P2X7 cation channel, with analogue 2-chloro-N-[1-(3-(nitrooxymethyl)phenyl)cyclohexyl)methyl]benzamide (56) exhibiting the best potency with an IC50 value of 0.39 μΜ.
- Durner, Anna,Koufaki, Maria,Kritsi, Eftichia,Nicke, Annette,Papakostas, Alexios,T. Pournara, Dimitra,Zoumpoulakis, Panagiotis
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supporting information
p. 2530 - 2543
(2020/10/19)
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- COMPOUNDS USEFUL FOR INHIBITING RAF DIMERS
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The disclosure provides compounds of Formula I (Formula I) (c) And the pharmaceutically acceptable salts thereof. The A, B, C, and D rings and the variables, RA, RB, RC, RD, L0, L1, L2
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Paragraph 0182
(2020/09/12)
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- KINASE INHIBITORS AND USES THEREOF
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This invention described herein relates to compounds of general formula (I) : (I), in which variable groups are as defined herein, and to their preparation and use. Uses for the compounds and for compositions containing them include treatment of cancer and other diseases mediated by protein kinases, such as Bcr-Abl kinase, and mutants thereof, such as the T315I mutant.
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Page/Page column 52
(2020/10/21)
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- Design, Synthesis, and Biological Evaluation of 3-(Imidazo[1,2- a]pyrazin-3-ylethynyl)-4-isopropyl- N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide as a Dual Inhibitor of Discoidin Domain Receptors 1 and 2
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Discoidin-domain receptors 1 and 2 (DDR1 and DDR2) are new potential targets for anti-inflammatory-drug discovery. A series of heterocycloalkynylbenzimides were designed and optimized to coinhibit DDR1 and DDR2. One of the most promising compounds, 5n, ti
- Wang, Zhen,Zhang, Yali,Pinkas, Daniel M.,Fox, Alice E.,Luo, Jinfeng,Huang, Huocong,Cui, Shengyang,Xiang, Qiuping,Xu, Tingting,Xun, Qiuju,Zhu, Dongsheng,Tu, Zhengchao,Ren, Xiaomei,Brekken, Rolf A.,Bullock, Alex N.,Liang, Guang,Ding, Ke,Lu, Xiaoyun
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p. 7977 - 7990
(2018/09/06)
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- 3-ACETYLENYL-PYRAZOLE-PYRIMIDINE DERIVATIVE, AND PREPARATION METHOD THEREFOR AND USES THEREOF
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The present invention relates to the field of chemical and medicine, more particularly, 3-ethynylpyrazolopyrimidine derivatives and their preparation methods and uses. The invention provides a 3-ethynylpyrazolopyrimidine derivative, and the structure is shown in formula I. The present invention also provides preparation methods and use of 3-ethynylpyrazolopyrimidine derivatives, comprising the compounds and derivatives, and their pharmaceutical compositions for the use of the treatment and prevention of tumors.
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Paragraph 0199; 200
(2017/11/10)
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- BIPHENYLCARBOXAMIDE DERIVATIVES AS HEDGEHOG PATHWAY MODULATORS
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The invention provides a method for modulating the activity of the hedgehog signaling pathway. In particular, the invention provides a method for inhibiting aberrant growth states resulting from phenotypes such as Ptc loss-of-function, hedgehog gain-of-fu
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Paragraph 0080; 0081
(2016/04/19)
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- HETEROCYCLIC MODULATORS OF LIPID SYNTHESIS AND COMBINATIONS THEREOF
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Heterocyclic modulators of lipid synthesis are provided as well as pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds; and methods of treating conditions characterized by disregulation of a fatty acid synthase pathway by the administration of such compounds and combinations of such compounds and other therapeutic agents.
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Page/Page column 86
(2015/07/07)
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- HETEROCYCLIC MODULATORS OF LIPID SYNTHESIS
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Heterocyclic modulators of lipid synthesis are provided as well as pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds; and methods of treating conditions characterized by disregulation of a fatty acid synthase pathway by the administration of such compounds.
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Page/Page column 71
(2014/01/18)
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- Electronically connected [n]helicenes: Synthesis and chiroptical properties of enantiomerically pure (E)-1,2-di([6]helicen-2-yl)ethenes
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We synthesized stilbenoid (E)-(P,P)- and (E)-(M,M)-[6]helicene dimers in enantiomerically pure form as part of a program aimed at the exploration of new strategies for the synthesis of large helicenes. The [2+2+2] cyclotrimerization of suitable triynes, r
- Roose, Jesse,Achermann, Stefan,Dumele, Oliver,Diederich, Francois
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supporting information
p. 3223 - 3231
(2013/07/05)
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- New 7-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one derivatives
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This invention is directed to new inhibitors of the p38 mitogen-activated protein kinase having the general formula (I), to pharmaceutical compositions comprising them, and to their use in therapy.
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Page/Page column 21
(2011/06/10)
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- NEW 7-PHENYL-[1,2,4]TRIAZOLO[4,3-A]PYRIDIN-3(2H)-ONE DERIVATIVES
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This invention is directed to new inhibitors of the p38 mitogen-activated protein kinase having the general formula (I), to processes for their preparation, to pharmaceutical compositions comprising them, and to their use in therapy.
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Page/Page column 36-37
(2011/06/16)
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- BIPHENYLCARBOXAMIDE DERIVATIVES AS HEDGEHOD PATHWAY MODULATORS
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The invention provides a method for modulating the activity of the hedgehog signaling pathway. In particular, the invention provides a method for inhibiting aberrant growth states resulting from phenotypes such as Ptc loss-of-function, hedgehog gain-of-function, smoothened gain-of-function or Gli gain-of-function, comprising contacting a cell with a sufficient amount of a compound of Formula I.
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- Rapid synthesis of Abelson tyrosine kinase inhibitors using click chemistry
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Protein kinases catalyze the phosphorylation of serine, threonine, tyrosine and histidine residues in proteins. Aberrant regulation of kinase activity has been implicated in many diseases including cancer. Thus development of new strategies for kinase inhibitor design remains an active area of research with direct relevance to drug development. Abelson (Abl) tyrosine kinase is one of the Src-family of tyrosine kinases and is directly implicated in Chronic Myelogenous Leukemia (CML). In this article, we have, for the first time, developed an efficient method for the construction of small molecule-based bisubstrate inhibitors of Abl kinase using click chemistry. Subsequent biochemical screenings revealed a set of moderately potent inhibitors, a few of which have comparable potency to Imatinib (an FDA-approved drug for treatment of chronic myeloid leukemia) against Abl.
- Kalesh, Karunakaran A.,Liu, Kai,Yao, Shao Q.
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experimental part
p. 5129 - 5136
(2010/04/04)
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- COMPOUNDS AND COMPOSITIONS AS HEDGEHOG PATHWAY MODULATORS
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The invention provides a method for modulating the activity of the hedgehog signaling pathway. In particular, the invention provides a method for inhibiting aberrant growth states resulting from phenotypes such as Ptc loss-of-function, hedgehog gain-of-fu
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Page/Page column 8-9
(2009/08/18)
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- NEW CHEMICAL COMPOUNDS
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The present invention encompasses compounds of general formula (1) wherein the groups R2 to R4, L, Q and n are defined as in claim 1, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and their use for preparing a pharmaceutical composition with the above-mentioned properties.
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Page/Page column 30-31
(2009/03/07)
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- New substituted spiro[cycloalkyl-1,3'-indo]-2'(1'H)-one derivatives and their use as p38 mitogen-activated kinase inhibitors
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This invention is directed to new inhibitors of the p38 mitogen-activated protein kinase having the general formula (I) to processes for their preparation; to pharmaceutical compositions comprising them; and to their use in therapy.
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Page/Page column 62
(2009/10/21)
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- NEW CHEMICAL COMPOUNDS
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The present invention encompasses compounds of general formula (1) wherein the groups R2 to R4, L, Q and n are defined as in claim 1, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and the use thereof for preparing a medicament having the above-mentioned properties.
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Page/Page column 30
(2008/12/07)
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- Synthesis and antialgal activity of dihydrophenanthrenes and phenanthrenes II: Mimics of naturally occurring compounds in Juncus effusus
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9,10-Dihydrophenanthrenes and phenanthrenes, mimics of natural compounds with strong antialgal activity, have been synthesized through cross-coupling by zerovalent Ni of 1-(2-iodo-5-methoxy)-phenylethanol or 2-iodo-5-methoxyacetophenone with iodoxylenes. The synthetic compounds had a hydroxyl or a methoxyl group at C-2 and two methyls in the C ring. Assays on the green alga Selenastrum capricornutum showed that all the compounds, except 2-methoxy-5,7-dimethylphenanthrene, caused strong inhibition of algal growth at 10-4 M. 2-Hydroxy-7,8-dimethyl-9,10-dihydrophenanthrene and 2-methoxy-5,6-dimethylphenanthrene fully inhibited growth at 10-5 M.
- Dellagreca,Fiorentino,Monaco,Pinto,Previtera,Zarrelli
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p. 257 - 271
(2007/10/03)
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- Palladium-catalyzed sequential alkylation - Alkenylation reactions and their application to the synthesis of fused aromatic rings
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The synthesis of fused aromatic carbocycles from aryl iodides and difunctional acceptors is outlined. This methodology is based on a palladium-catalyzed aromatic substitution followed by an intramolecular Heck sequence. Under the optimized conditions (Pd(OAc)2 (10 mol %), tri-2-furylphosphine (20-30 mol %), norbornene (2 equiv), Cs2CO3 (2 equiv), CH3CN, reflux), bromoenoates react with aryl iodides bearing numerous substituents (F, Cl, CF3, Me, etc.). The expanded description of our initial work as well as the use of polysubstituted aryl iodides is described.
- Lautens, Mark,Paquin, Jean-Francois,Piguel, Sandrine,Dahlmann, Marc
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p. 8127 - 8134
(2007/10/03)
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- Coupling reactions of ortho-substituted halobenzenes with alkynes. The synthesis of phenylacetylenes and symmetrical or unsymmetrical 1,2-diphenylacetylenes
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The Pd- or Pd/Cu-catalyzed coupling reactions of halobenzenes bearing the methyl, hydroxymethyl, acetoxymethyl, methoxycarbonyl, or both methoxy and 4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl groups in the ortho-position with gaseous or metallated acetylene, (trialkylsilyl)acetylenes, and arylacetylenes have been systematically studied. Various functionalized aryl- or diarylacetylenes have been synthesized in good to excellent yields. Whereas additional fluoro, nitro, or methoxy group attached to the benzene ring does not interfere in the coupling reactions, the presence of a methoxycarbonyl requires a careful optimization of reaction conditions to achieve moderate yields.
- Stara, Irena G.,Stary, Ivo,Kollarovic, Adrian,Teply, Filip,Saman, David,Fiedler, Pavel
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p. 649 - 672
(2007/10/03)
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