- Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor
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As regulators of transcription, epigenetic proteins that interpret post-translational modifications to N-terminal histone tails are essential for maintaining cellular homeostasis. When dysregulated, "reader" proteins become drivers of disease. In the case of bromodomains, which recognize N-?-acetylated lysine, selective inhibition of individual bromodomain-and-extra-terminal (BET)-family bromodomains has proven challenging. We describe the >55-fold N-terminal-BET bromodomain selectivity of 1,4,5-trisubstituted-imidazole dual kinase-bromodomain inhibitors. Selectivity for the BRD4 N-terminal bromodomain (BRD4(1)) over its second bromodomain (BRD4(2)) arises from the displacement of ordered waters and the conformational flexibility of lysine-141 in BRD4(1). Cellular efficacy was demonstrated via reduction of c-Myc expression, inhibition of NF-κB signaling, and suppression of IL-8 production through potential synergistic inhibition of BRD4(1) and p38α. These dual inhibitors provide a new scaffold for domain-selective inhibition of BRD4, the aberrant function of which plays a key role in cancer and inflammatory signaling.
- Divakaran, Anand,Talluri, Siva K.,Ayoub, Alex M.,Mishra, Neeraj K.,Cui, Huarui,Widen, John C.,Berndt, Norbert,Zhu, Jin-Yi,Carlson, Angela S.,Topczewski, Joseph J.,Schonbrunn, Ernst K.,Harki, Daniel A.,Pomerantz, William C. K.
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- COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF RESPIRATORY DISEASES
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The present invention relates to new compounds that are useful in the prevention or treatment of respiratory diseases, such as asthma, acute and chronic inflammatory conditions, and fibrotic diseases or conditions in which fibrosis contributes to the pathology of the condition. The invention also relates to the preparation of the compounds, and to compositions including the compounds. The present invention also relates to the use of the compounds, as well as compositions including the compounds, in treating or preventing respiratory diseases, acute and chronic inflammatory conditions, and fibrotic diseases or conditions in which fibrosis contributes to the pathology of the condition.
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Page/Page column 75; 78; 80; 94
(2020/06/01)
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- COMPOUNDS FOR THE TREATMENT OF RESPIRATORY DISEASES
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The present invention relates to new compounds that are useful in the prevention or treatment of respiratory diseases, such as asthma, to the preparation of the compounds, and to compositions including the compounds. The present invention also relates to the use of the compounds, as well as compositions including the compounds, in treating or preventing respiratory diseases.
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Page/Page column 87
(2018/11/26)
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- 2-IMIDAZOLYL-PYRIMIDINE SCAFFOLDS AS POTENT AND SELECTIVE INHIBITORS OF NEURONAL NITRIC OXIDE SYNTHASE
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Imidazolyl-pyrimidine and related compounds, as can utilize heme-iron coordination in the selective inhibition of neuronal nitric oxide synthase.
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Paragraph 0024
(2016/01/25)
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- A versatile synthesis of novel pan-PIM kinase inhibitors with initial SAR study
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Herein, we describe the versatile synthesis of (Z)-5-((2-aminopyrimidin-4-yl)methylene)thiazolidine-2,4-dione inhibitors (1) of the PIM family of kinases. This chemistry strategy was a key element in the multi-variable optimization program with the goal of identifying high quality leads for the development of a treatment for cancer.
- Flanders, Yvonne,Dumas, Stephane,Caserta, Justin,Nicewonger, Robb,Baldino, Michael,Lee, Chee-Seng,Baldino, Carmen M.
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p. 3186 - 3190
(2015/06/02)
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- Novel 2,4-disubstituted pyrimidines as potent, selective, and cell-permeable inhibitors of neuronal nitric oxide synthase
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Selective inhibition of neuronal nitric oxide synthase (nNOS) is an important therapeutic approach to target neurodegenerative disorders. However, the majority of the nNOS inhibitors developed are arginine mimetics and, therefore, suffer from poor bioavai
- Mukherjee, Paramita,Li, Huiying,Sevrioukova, Irina,Chreifi, Georges,Martásek, Pavel,Roman, Linda J.,Poulos, Thomas L.,Silverman, Richard B.
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p. 1067 - 1088
(2015/03/04)
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- NEW THIENOPYRIMIDINE DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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Compounds of formula (I): wherein R1, R2, R3, R4, R5, R6, R7, R12, X, A and n are as defined in the description.
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Page/Page column 135
(2015/07/15)
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- Aminopyrimidine Kinase Inhibitors
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Disclosed are compounds, pharmaceutical compositions containing those compounds, and uses of the compounds and compositions as modulators of casein kinase 1 (e.g., CK1γ), casein kinase 2 (CK2), Pim-1, Pim-2, Pim-3, the TGFβ pathway, the Wnt pathway, the J
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- IMIDAZOLE-2, 4-DIONE INHIBITORS OF CASEIN KINASE 1
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Disclosed are compounds, pharmaceutical compositions containing those compounds, and uses of the compounds and compositions as modulators of casein kinase 1 (e.g., CK1γ), the TGFβ pathway and/or the Wnt pathway. Uses are also disclosed for the treatment o
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- Aminopyrimidine Kinase Inhibitors
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Disclosed are compounds, pharmaceutical compositions containing those compounds, and uses of the compounds and compositions as modulators of casein kinase 1 (e.g., CK1γ), casein kinase 2 (CK2), Pim 1, Pim2, Pim3, the TGFβ pathway, the Wnt pathway, the JAK
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Page/Page column 67
(2011/07/06)
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- 6,7-Dihydro-5H-pyrazolo[1,2-a]pyrazol-1-ones which control inflammatory cytokines
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The present invention relates to methods for treating diseases or disease states which are mediated or otherwise affected by the extracellular release of cytokines, said method comprising the step of administering to a human or higher mammal in need of treatment, one or more of the 6,7-dihydro-5H-pyrazolo[1,2a]pyrazol-1-ones of the present invention.
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- Bicyclic pyrazolone cytokine inhibitors
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The present invention relates to 6,7-dihydro-5H-pyrazolo[1,2a]pyrazol-1-ones which inhibit the extracellular release of inflammatory cytokines, said cytokines responsible for one or more human or higher mammalian disease states. The present invention furt
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Page/Page column 20
(2008/06/13)
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- 6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-ones which control inflammatory cytokines
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The present invention relates to compounds which are capable of preventing the extracellular release of inflammatory cytokines, said compounds, including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, have the formula: wherein R1 is substituted aryl; R4 is substituted or unsubstituted aryl or heteroaryl.
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- 6,7-Dihydro-5H-pyrazolo[1,2-a]pyrazol-1-ones which provide analgesia
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The present invention relates to compound which are capable of preventing the extracellular release of inflammatory cytokines, said compounds, including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, have the formula: 1wherein R comprises ethers or amines; R1 is: a) substituted or unsubstituted aryl; or b) substituted or unsubstituted heteroaryl; each R2 unit is independently selected from the group consisting of: a) hydrogen; b) —(CH2)jO(CH2)nR8; c) —(CH2)jNR9aR9b; d) —(CH2)jCO2R10; e) —(CH2)jOCO2R10 f) —(CH2)jCON(R10)2; g) —(CH2)jOCON(R10)2; h) two R2 units can be taken together to form a carbonyl unit; i) and mixtures thereof; R8, R9a, R9b, and R10 are each independently hydrogen, C1-C4 alkyl, and mixtures thereof; R9a and R9b can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two R10 units can be take together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5, n is an index from 0 to 5; Z is O, S, NR11, or NOR11; R11 is hydrogen or C1-C4 alkyl.
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- 1,2-dihydropyrazol-3-ones which controls inflammatory cytokines
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The present invention relates to compounds which are capable of preventing the extracellular release of inflammatory cytokines, said compounds, or enantiomeric and diasteriomeric forms or pharmaceutically acceptable salts thereof, have the formula: wherein R is an ether or amino unit, R1 is substituted phenyl, each R2 and R3 unit is independently selected from the group consisting of: a) hydrogen; and b) substituted or unsubstituted C1-C10 hydrocarbyl selected from the group consisting of: i) C1-C10 linear, branched or cyclic alkyl; ii) C1-C10 aryl; iii) C1-C10 heterocyclic; iv) C1-C10 heteroaryl.
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- Process for making pyridyl and pyrimidine substituted imidazole compounds
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1,4,5,-substituted imidazole compounds and compositions for use in therapy as cytokine inhibitors.
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- Cycloalkyl substituted imidazoles
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1,4,5-substituted imidazole compounds and compositions for use in therapy.
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- Cycloalkyl substituted imidazoles
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Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy.
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- Substituted imidazole compounds
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Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as cytokine inhibitors.
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- Phenoxypyrimidine inhibitors of p38α kinase: Synthesis and statistical evaluation of the p38 inhibitory potencies of a series of 1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl) imidazoles
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As a continuation of our work with 1,4,5 substituted imidazole inhibitors of p38α, we report a series of 1-(4-piperidinyl)-4-(4-fluorophenyl)-5-(2-phenoxy-4-pyrimidinyl) imidazoles related to 7. The compounds have IC50's for inhibition of p38α ranging from 6.0 to 650 nM. Statistical analysis of the p38α inhibitor potencies shows a correlation of IC50's with the electron donating strength of low molecular weight substituents.
- Boehm, Jeffrey C.,Bower, Michael J.,Gallagher, Timothy F.,Kassis, Shouki,Johnson, Stephen R.,Adams, Jerry L.
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p. 1123 - 1126
(2007/10/03)
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- Substituted imidazole compounds
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Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as cytokine inhibitors.
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- First study of syntheses and reactivity of Grignard compounds in the diazine series. Diazines. Part 27
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A preparation of Grignard derivatives of diazines is described using a halogen magnesium exchange reaction. This convenient method allows the functionalization of these rings at 0°C or even room temperature.
- Leprêtre,Turck,Plé,Knochel,Quéguiner
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p. 265 - 273
(2007/10/03)
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- Substituted imidazole compounds
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This invention relates to a novel group of imidazole compounds, processes for the preparation thereof, the use thereof in treating cytokine mediated diseases and pharmaceutical compositions for use in such therapy.
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- Cycloalkyl substituted imidazoles
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Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy.
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- Imidazole compounds and compositions
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Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as cytokine inhibitors.
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- Substituted imidazole compounds
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Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as cytokine inhibitors.
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- Substituted imidazole compounds
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Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as cytokine inhibitors.
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- Pyrimidinylimidazole inhibitors of CSBP/P38 kinase demonstrating decreased inhibition of hepatic cytochrome P450 enzymes
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Pyrimidine analogs of the pyridinylimidazole class of CSBP/p38 kinase inhibitors were prepared in an effort to reduce the potent inhibition of hepatic cytochrome P450 observed for the pyridinyl compounds. The substitution of pyrimidin-4-yl, 2-methoxypyrimidin-4-yl, or 2- methylaminopyrimidin-4-yl for pyridin-4-yl effectively dissociates CSBP/p38 kinase from P450 inhibition for this series and furthermore achieves an increase in oral activity.
- Adams, Jerry L.,Boehm, Jeffrey C.,Kassis, Shouki,Gorycki, Peter D.,Webb, Edward F.,Hall, Ralph,Sorenson, Margaret,Lee, John C.,Ayrton, Andrew,Griswold, Don E.,Gallagher, Timothy F.
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p. 3111 - 3116
(2007/10/03)
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- Imidazole compounds, compositions and use
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Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as cytokine inhibitors.
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- Imidazole compounds, use and process of making
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Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as cytokine inhibitors.
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- Compounds
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Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as cytokine inhibitors.
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- Pyridyl imidazole compounds and compositions
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Novel 1, 4, 5-substituted imidazole compounds and compositions for use in therapy as cytokine inhibitors.
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