- NEW COMPOUNDS FOR TREATMENT OF DISEASES RELATED TO DUX4 EXPRESSION
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The present invention relates to compounds for the treatment of diseases related to DUX4 expression, such as muscular dystrophies. It also relates to use of such compounds, or to methods of use of such compounds.
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Page/Page column 58; 85
(2021/06/04)
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- THERAPEUTIC METHODS AND COMPOUNDS
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The invention provides a compound of formula I: (I) or a pharmaceutically acceptable salt thereof, wherein R1-R5 Y have any of the values described in the specification, as well as compositions comprising a compound of formula I. The compounds are useful to treat malaria.
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Page/Page column 20-22
(2020/11/03)
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- Syntheses and structure-activity relationships for some triazolyl p38α MAPK inhibitors
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The design, synthesis and biological evaluation of novel triazolyl p38α MAPK inhibitors with improved water solubility for formulation in cationic liposomes (SAINT-O-Somes) targeted at diseased endothelial cells is described. Water-solubilizing groups wer
- Seerden, Jean-Paul G.,Leusink-Ionescu, Gabriela,Leguijt, Robin,Saccavini, Catherine,Gelens, Edith,Dros, Bas,Woudenberg-Vrenken, Titia,Molema, Grietje,Kamps, Jan A.A.M.,Kellogg, Richard M.
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p. 1352 - 1357
(2014/03/21)
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- Design and synthesis of minimalist terminal alkyne-containing diazirine photo-crosslinkers and their incorporation into kinase inhibitors for cell- and tissue-based proteome profiling
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Less is more: A minimalist "clickable" photo-crosslinker (see scheme) was incorporated with numerous small-molecule kinase inhibitors. The resulting probes were used for both in vitro (cell lysates) and in situ (live cells) proteome profiling, for large-scale identification of their potential cellular kinase targets and shows improved outcomes over previous probes. Copyright
- Li, Zhengqiu,Hao, Piliang,Li, Lin,Tan, Chelsea Y. J.,Cheng, Xiamin,Chen, Grace Y. J.,Sze, Siu Kwan,Shen, Han-Ming,Yao, Shao Q.
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p. 8551 - 8556
(2013/09/12)
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- Ligand-protein interactions of selective casein kinase 1δ inhibitors
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Casein kinase 1δ (CK1δ) and 1ε (CK1ε) are believed to be necessary enzymes for the regulation of circadian rhythms in all mammals. On the basis of our previously published work demonstrating a CK1ε-preferring compound to be an ineffective circadian clock modulator, we have synthesized a series of pyrazole-substitued pyridine inhibitors, selective for the CK1δ isoform. Additionally, using structure-based drug design, we have been able to exploit differences in the hinge region between CK1δ and p38 to find selective inhibitors that have minimal p38 activity. The SAR, brain exposure, and the effect of these inhibitors on mouse circadian rhythms are described. The in vivo evaluation of these inhibitors demonstrates that selective inhibition of CK1δ at sufficient central exposure levels is capable of modulating circadian rhythms.
- Mente, Scot,Arnold, Eric,Butler, Todd,Chakrapani, Subramanyam,Chandrasekaran, Ramalakshmi,Cherry, Kevin,Dirico, Ken,Doran, Angela,Fisher, Katherine,Galatsis, Paul,Green, Michael,Hayward, Matthew,Humphrey, John,Knafels, John,Li, Jianke,Liu, Shenping,Marconi, Michael,McDonald, Scott,Ohren, Jeff,Paradis, Vanessa,Sneed, Blossom,Walton, Kevin,Wager, Travis
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p. 6819 - 6828
(2013/10/01)
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- Regiocontrolled synthesis of 3- and 5-aminopyrazoles, pyrazolo[3,4-d] pyrimidines, pyrazolo[3,4-b]pyridines and pyrazolo[3,4-b]quinolinones as MAPK inhibitors
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Microwave irradiation of a hydrazine and 3-methoxyacrylonitrile, ethoxymethylenemalononitrile or ethyl acetoacetate provides rapid access to 3- or 5-substituted pyrazoles in excellent yield and with total regiocontrol in a process that can be switched from one regioisomer to the other by choice of conditions. Subsequent reaction, either by microwave-assisted hydrolysis and cyclocondensation with formamide, Hantzsch-type three-component reaction with an aldehyde and ketone, or by cyclocondensation with 2-nitrobenzaldehyde, provides the pyrazolo[3,4-d]pyrimidine, pyrazolo[3,4-b]pyridine or pyrazolo[3,4-b] quinolin-4-one framework, respectively, of inhibitors of mitogen-activated protein kinases.
- Bagley, Mark C.,Baashen, Mohammed,Paddock, Victoria L.,Kipling, David,Davis, Terence
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p. 8429 - 8438
(2013/09/02)
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- Chemical probes of a trisubstituted pyrrole to identify its protein target(s) in Plasmodium sporozoites
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Malaria is a disease that has a major impact in many developing nations, especially on the African continent. There is a need to develop new therapeutics and prophylactic treatments against it. A trisubstituted pyrrole was recently found to inhibit infect
- Towle, Tyrell,Chang, Isabel,Kerns, Robert J.,Bhanot, Purnima
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supporting information
p. 1874 - 1877
(2013/04/10)
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- Identification of SD-0006, a potent diaryl pyrazole inhibitor of p38 MAP kinase
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Starting from an initial HTS screening lead, a novel series of C(5)-substituted diaryl pyrazoles were developed that showed potent inhibition of p38α kinase. Key to this outcome was the switch from a pyridyl to pyrimidine at the C(4)-position leading to analogs that were potent in human whole blood based cell assay as well as in a number of animal efficacy models for rheumatoid arthritis. Ultimately, we identified a clinical candidate from this substrate; SD-0006.
- Walker, John K.,Selness, Shaun R.,Devraj, Rajesh V.,Hepperle, Michael E.,Naing, Win,Shieh, Huey,Kurambail, Ravi,Yang, Syaulan,Flynn, Daniel L.,Benson, Alan G.,Messing, Dean M.,Dice, Tom,Kim, Tina,Lindmark,Monahan, Joseph B.,Portanova, Joseph
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scheme or table
p. 2634 - 2638
(2010/07/13)
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- The application of flow microreactors to the preparation of a family of casein kinase i inhibitors
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In this article we demonstrate how a combination of enabling technologies such as flow synthesis, solid-supported reagents and scavenging resins utilised under fully automated software control can assist in typical medicinal chemistry programmes. In particular automated continuous flow methods have greatly assisted in the optimisation of reaction conditions and facilitated scale up operations involving hazardous chemical materials. Overall a collection of twenty diverse analogues of a casein kinase I inhibitor has been synthesised by changing three principle binding vectors.
- Venturoni, Francesco,Nikbin, Nikzad,Ley, Steven V.,Baxendale, Ian R.
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experimental part
p. 1798 - 1806
(2010/08/07)
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- Pyridinylquinoxalines and pyridinylpyridopyrazines as lead compounds for novel p38α mitogen-activated protein kinase inhibitors
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Various substituted 2(3)-(4-fluorophenyl)-3(2)-(pyridin-4-yl)quinoxalines and 2(3)-(4-fluorophenyl)-3(2)-(pyridin-4-yl)pyridopyrazines were synthesized as novel p38α MAP kinase inhibitors via different short synthetic strategies with high variation possibilities. The formation of the quinoxaline/ pyridopyrazine core was achieved from α-diketones and o-phenylenediamines/ α-diaminopyridines under microwave irradiation. Introduction of an amino moiety at the pyridine C2 position of the 2(3)-(4-fluorophenyl)-3(2)-(pyridin-4- yl)quinoxalines led to compounds showing potent enzyme inhibition down to the double-digit nanomolar range (6f; IC50 = 81 nM). Replacement of the quinoxaline core with pyrido[2,3-b]pyrazine gave compound 9e with superior p38α MAP kinase inhibition (IC50= 38 nM).
- Koch, Pierre,Jahns, Hartmut,Schattel, Verena,Goettert, Marcia,Laufer, Stefan
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supporting information; experimental part
p. 1128 - 1137
(2010/08/05)
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- From five- to six-membered rings: 3,4-Diarylquinolinone as lead for novel p38MAP kinase inhibitors
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In this study we describe the design, synthesis, and biological evaluation of 3-(4-fluorophenyl)-4-pyridin-4-ylquinoline-2(1H)-one (5) as a new inhibitor of MAPK with a p38αMAPK IC50 of 1.8 μM. By keeping the common vicinal pyridine/4-F-phenyl
- Peifer, Christian,Kinkel, Katrin,Abadleh, Mohammed,Schollmeyer, Dieter,Laufer, Stefan
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p. 1213 - 1221
(2007/10/03)
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- HETEROCYCLIC COMPOUNDS
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New compounds of formula (I), wherein the meanings for the various substituents are as disclosed in the description. These compounds are useful as p38 kinase inhibitors.
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Page/Page column 42
(2008/06/13)
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- Synthesis and biological activities of 4-phenyl-5-pyridyl-1,3-thiazole derivatives as p38 MAP kinase inhibitors
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A novel series of 4-phenyl-5-pyridyl-1,3-thiazole analogues possessing potent in vitro inhibitory activity against p38 mitogen-activated protein kinase and the release of tumor necrosis factor-α (TNF-α) from human monocytic THP-1 cells stimulated by lipopolysaccharide has been identified. Subsequent structure-activity relationship (SAR) studies and optimization for absorption, distribution, metabolism, and elimination (ADME) profiles led to the identification of compounds 7g and 10b as orally active lead candidates that block the in vivo production of proinflammatory cytokine (TNF-α). In pharmacokinetic studies, compound 10b showed good oral administration in mice and demonstrated significant in vivo anti-inflammatory activity in an anti-collagen monoclonal antibody-induced arthritis mouse model (minimum effective dose (MED)=30 mg/kg). Further elucidation of this class of compounds may provide novel anti-inflammatory agents, such as anti-rheumatoid arthritis drugs.
- Miwatashi, Seiji,Arikawa, Yasuyoshi,Naruo, Ken-Ichi,Igaki, Keiko,Watanabe, Yasumasa,Kimura, Hiroyuki,Kawamoto, Tomohiro,Ohkawa, Shigenori
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p. 410 - 418
(2007/10/03)
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- Substituted pyrazoles as p38 kinase inhibitors
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A class of pyrazole derivatives is described for use in treating p38 kinase mediated disorders. Compounds of particular interest are defined by Formula (IA), wherein R1, R2, R3 and R4 are as described in the spe
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Page/Page column 162
(2010/02/15)
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- Synthesis and SAR of 2,3-diarylpyrrole inhibitors of parasite cGMP-dependent protein kinase as novel anticoccidial agents
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Several analogs of 2,3-diaryl pyrroles were synthesized and evaluated as inhibitors of Eimeria tenella cGMP-dependent protein kinase and in in vivo anticoccidial assays. A 4-fluorophenyl group enhances both in vitro and in vivo activities. The most potent
- Biftu, Tesfaye,Feng, Dennis,Ponpipom, Mitree,Girotra, Narindar,Liang, Gui-Bai,Qian, Xiaoxia,Bugianesi, Robert,Simeone, Joseph,Chang, Linda,Gurnett, Anne,Liberator, Paul,Dulski, Paula,Leavitt, Penny Sue,Crumley, Tami,Misura, Andrew,Murphy, Terence,Rattray, Sandra,Samaras, Samantha,Tamas, Tamas,Mathew, John,Brown, Christine,Thompson, Don,Schmatz, Dennis,Fisher, Michael,Wyvratt, Matthew
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p. 3296 - 3301
(2007/10/03)
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- PYRAZOLOPYRIDINE DERIVATES
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New compounds of formula (I) and the salts, solvates and prodrugs thereof, wherein the meanings for the various substituents are as disclosed in the description. These compounds are useful as p38 kinase inhibitors.
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- MEDICINAL COMPOSITIONS
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The present invention relates to an agent for the prophylaxis or treatment of pain, an agent for suppressing activation of osteoclast, and an inhibitor of osteoclast formation, which contains a p38 MAP kinase inhibitor and/or a TNF-α production inhibitor.
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- Aliphatic hydroxy substituted piperidyl diaryl pyrrole derivatives as antiprotozoal agents
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Trisubstituted pyrroles are antiprotozoal agents useful in the treatment and prevention of protozoal diseases in human and animals, including the control of coccidiosis in poultry.
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- CONCOMITANT DRUGS
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The present invention relates to a pharmaceutical agent containing one or more kinds of a p38 MAP kinase inhibitor and/or a TNF-α production inhibitor and one or more kinds of drugs selected from the group consisting of (1) a non-steroidal antiinflammator
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- 2-SUBSTITUTED ARYL PYRROLES, COMPOSITIONS CONTAINING SUCH COMPOUNDS AND METHODS OF USE
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The present invention addresses 2-substituted aryl pyrroles, as well as compositions containing such compounds and methods of treatment. Cytokine mediated diseases refers to diseases or conditions in which excessive or unregulated production or activity o
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- Imidazopyrimidines, potent inhibitors of p38 MAP kinase
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The MAP kinase p38 is implicated in the release of the pro-inflammatory cytokines TNF-α and IL-1β. Inhibition of cytokine release may be a useful treatment for inflammatory conditions such as rheumatoid arthritis and Crohn's disease. A novel series of imidazopyrimidines have been discovered that potently inhibit p38 and suppress the production of TNF-α in vivo.
- Rupert, Kenneth C.,Henry, James R.,Dodd, John H.,Wadsworth, Scott A.,Cavender, Druie E.,Olini, Gilbert C.,Fahmy, Bohumila,Siekierka, John J.
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p. 347 - 350
(2007/10/03)
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- Imidazolyl-cyclic acetals
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Compounds of formula (I) are described in which R1is optionally substituted heteroaryl; R2is optionally substituted aryl or optionally substituted heteroaryl; R3is a group —L1—R7or —L2—Rsu
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- Aliphatic amine substituted piperidyl diaryl pyrrole derivatives as antiprotozoal agents
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Trisubstituted pyrroles are antiprotozoal agents useful in the treatment and prevention of protozoal diseases in human and animals, including the control of coccidiosis in poultry.
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- p38MAP KINASE INHIBITORS
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A 1,3-thiazole compound substituted at the 5-position by a pyridyl group optionally having substituent(s) has a superior p38 MAP kinase inhibitory activity and TNF-α production inhibitory activity.
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- Design, synthesis and bioactivities of novel diarylthiophenes: Inhibitors of tumor necrosis factor-α (TNF-α) production
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The design, synthesis and SAR of novel diarylthiophene derivatives were performed. These compounds were designed by structural hybridization of TNF-α production inhibitors bearing 4-fluorophenyl and 4-pyridyl groups such as FR133605, FR167653 and SB210313
- Fujita, Masakazu,Hirayama, Tetsuya,Ikeda, Naoko
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p. 3113 - 3122
(2007/10/03)
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- Diaryl piperidyl pyrrole derivatives as antiprotozoal agents
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Trisubstituted pyrroles are antiprotozoal agents useful in the treatment and prevention of protozoal diseases in human and animals, including the control of coccidiosis in poultry.
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- 2-substituted aryl pyrroles, compositions containing such compounds and methods of use
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The present invention addresses 2-substituted aryl pyrroles, as well as compositions containing such compounds and methods of treatment. Cytokine mediated diseases refers to diseases or conditions in which excessive or unregulated production or activity o
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- Regulation of stress-induced cytokine production by pyridinylimidazoles inhibition of CSBP kinase
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Members of three classes of pyridinylimidazoles bind with varying affinities to CSBP (p38) kinase which is a member of a stress-induced signal transduction pathway. Based upon SAR and protein homology modeling, the pharmacophore and three potential modes of binding to the enzyme are presented. For a subset of pyridinylimidazoles, binding is shown to correlate with inhibition of CSBP kinase activity, whereas no significant inhibition of PKA, PKα and ERK kinase activity is observed.
- Gallagher, Timothy F.,Seibel, George L.,Kassis, Shouki,Laydon, Jeffrey T.,Blumenthal, Mary Jane,Lee, John C.,Lee, Dennis,Boehm, Jeffrey C.,Fier-Thompson, Susan M.,Abt, Jeffrey W.,Soreson, Margaret E.,Smietana, Juanita M.,Hall, Ralph F.,Garigipati, Ravi S.,Bender, Paul E.,Erhard, Karl F.,Krog, Arnold J.,Hofmann, Glenn A.,Sheldrake, Peter L.,McDonnell, Peter C.,Kumar, Sanjay,Young, Peter R.,Adams, Jerry L.
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- 3-(heteroaryl)-pyrazololi[1,5-a]pyrimidines
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This invention relates to heterocyclic derivatives useful for inhibiting the production of Interleukin-1 (IL-1) and tumor necrosis factor (TNF) and the like, which can be represented by the following formula: STR1 to a process for their production, to a pharmaceutical composition containing the same and to uses thereof.
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- ANTIPSYCHOTIC 1-CYCLOALKYLPIPERIDINES
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There are provided cycloalkyl piperidine compounds which are useful in the treatment of physiological or drug-induced psychosis or dyskinesia in a mammal. These novel compounds are selective sigma receptor antagonists and have a low potential for movement
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- Novel piperidine σ receptor ligands as potential antipsychotic drugs
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σ receptor ligands represent a new class of potential antipsychotic drugs. This paper presents the structure-activity relationships leading to novel disubstituted piperidine σ ligands, which have little or no affinity for dopamine D2 receptors. Selectivity for σ sites over dopamine D2 or serotonin 5-HT2 receptors appears to be governed by the chemical nature of the piperidine nitrogen substituent, its distance from the basic nitrogen, and its orientation relative to the other piperidine substituent. Several of these compounds have good oral potency in some animal models used to evaluate potential antipsychotic drugs. The N-cyclopropylmethyl ketones and ethers (e.g. 6i (DuP 734), 6q, 18a, and 18n) have the best in vivo potency. Compounds 6i (DuP 734) and 6q did not cause catalepsy in the rat, even at very high doses. On the basis of the pharmacology profiles of these σ ligands, we propose these compounds may be effective antipsychotic drugs, which do not induce extrapyramidal side effects or tardive dyskinesia.
- Gilligan,Cain,Christos,Cook,Drummond,Johnson,Kergaye,McElroy,Rohrbach,Schmidt,Tam
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p. 4344 - 4361
(2007/10/02)
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