- Design of adenosine kinase inhibitors from the NMR-based screening of fragments
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A strategy is described for designing high-affinity ligands using information derived from the NMR-based screening of fragments. The method involves the fragmentation of an existing lead molecule, identification of suitable replacements for the fragments, and incorporation of the newly identified fragments into the original scaffold. Using this technique, novel substituents were rapidly identified and incorporated into lead inhibitors of adenosine kinase that exhibited potent in vitro and in vivo activities. This approach is a valuable strategy for modifying existing leads to improve their potency, bioavailability, or toxicity profile and thus represents a useful technique for lead optimization.
- Hajduk,Gomtsyan,Didomenico,Cowart,Bayburt,Solomon,Severin,Smith,Walter,Holzman,Stewart,McGaraughty,Jarvis,Kowaluk,Fesik
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- NOVEL COMPOUNDS AS NADPH OXIDASE INHIBITORS
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The present invention is related to new compounds, pharmaceutical composition thereof and to their use for the treatment and/or prophylaxis of disorders or conditions related to Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase).
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Paragraph 0288; 0289
(2020/04/09)
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- Compound capable of effectively inhibiting or killing multi-drug resistant bacteria and preparation method and application of compound
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The invention discloses a compound capable of effectively inhibiting or killing bacterial microorganisms. The compound has a structural general formula shown as the formula I (please see the formula in the description). Pharmacodynamic experiments prove that the compound can effectively inhibit or kill the broad-spectrum and multi-drug resistant staphylococcus aureus, streptococcus pneumoniae and staphylococcus aureus and is expected to be developed into a novel effective antibacterial drug with new targets.
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Paragraph 0182; 0691
(2017/06/02)
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- PYRIMIDINE-2-AMINE COMPOUNDS AND THEIR USE AS INHIBITORS OF JAK KINASES
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This invention is directed to compounds of formula (I): where, n, m, Y, R1, R2, R3, R4 and R5 are disclosed herein, as isolated stereoisomers or mixtures thereof, or as pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising the compounds of formula (I); and methods of using the compounds and the pharmaceutical compositions in treating diseases or conditions associated with JAK2 activity.
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Page/Page column 174-175
(2009/10/09)
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- INHIBITORS OF HISTONE DEACETYLASE
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The invention relates to a series of compounds useful for inhibiting histone deacetylase (HDAC) enzymatic activity. The invention also provides a method for inhibiting histone descetylase in a cell using said compounds as well as a method for treating cell proliferative diseases and conditions using said HDAC inhibitors. Further, the invention provides pharmaceutical compositions comprising the HDAC inhibiting compounds and a pharmaceutically acceptable carrier.
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Page/Page column 71-72
(2010/02/14)
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- 5-(3-Bromophenyl)-7-(6-morpholin-4-ylpyridin-3-yl)pyrido[2,3-d] pyrimidin-4-ylamine: Structure-activity relationships of 7-substituted heteroaryl analogs as non-nucleoside adenosine kinase inhibitors
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4-Amino-5,7-disubstituted pyridopyrimidines are potent, non-nucleoside inhibitors of adenosine kinase (AK). We recently identified a potent, orally efficacious analog, 4 containing a 7-pyridylmorpholine substituted ring system as the key structural element of this template. In this report, we disclose the pharmacologic effects of five- and six-membered heterocyclic ring replacements for the pyridine ring in 4. These replacements were found to have interesting effects on in vivo efficacy and genotoxicity as well as in vitro potency. We discovered that the nitrogen in the heterocyclic ring at C(7) is important for the modulation of mutagenic side effects (Ames assay).
- Matulenko, Mark A.,Lee, Chih-Hung,Jiang, Meiqun,Frey, Robin R.,Cowart, Marlon D.,Bayburt, Erol K.,DiDomenico Jr., Stanley,Gfesser, Gregory A.,Gomtsyan, Arthur,Guo, Zhu Zheng,McKie, Jeffery A.,Stewart, Andrew O.,Yu, Haixia,Kohlhaas, Kathy L.,Alexander, Karen M.,McGaraughty, Steve,Wismer, Carol T.,Mikusa, Joseph,Marsh, Kennan C.,Snyder, Ronald D.,Diehl, Marilyn S.,Kowaluk, Elizabeth A.,Jarvis, Michael F.,Bhagwat, Shripad S.
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p. 3705 - 3720
(2007/10/03)
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- Synthesis and biological evaluation of pteridine and pyrazolopyrimidine based adenosine kinase inhibitors
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Three new approaches have been tested to modify existing pyridopyrimidine and alkynylpyrimidine classes of nonnucleoside adenosine kinase inhibitors 2 and 3. 4-Amino-substituted pteridines 8a-e were generally less active than corresponding 5- and 6-substituted pyridopyrimidines 2. Pyrazolopyrimidine 13c with IC50=7.5nM was superior to its open chain alkynylpyrimidine analog 13g (IC50=22nM) while pyrrolopyrimidines such as 17a were inactive.
- Gomtsyan, Arthur,Didomenico, Stanley,Lee, Chih-Hung,Stewart, Andrew O.,Bhagwat, Shripad S.,Kowaluk, Elizabeth A.,Jarvis, Michael F.
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p. 4165 - 4168
(2007/10/03)
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- Discovery of 4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido [2,3-d]pyrimidine, an orally active, non-nucleoside adenosine kinase inhibitor
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Adenosine (ADO) is an endogenous homeostatic inhibitory neuromodulator that reduces cellular excitability at sites of tissue injury and inflammation. Inhibition of adenosine kinase (AK), the primary metabolic enzyme for ADO, selectively increases ADO concentrations at sites of tissue trauma and enhances the analgesic and antiinflammatory actions of ADO. Optimization of the high-throughput screening lead, 4-amino-7-aryl-substituted pteridine (5) (AK IC50 = 440 nM), led to the identification of compound 21 (4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido [2,3-d]pyrimidine, ABT-702), a novel, potent (AK IC50 = 1.7 nM) nonnucleoside AK inhibitor with oral activity in animal models of pain and inflammation.
- Lee,Jiang,Cowart,Gfesser,Perner,Ki Hwan Kim,Yu Gui Gu,Williams,Jarvis,Kowaluk,Stewart,Bhagwat
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p. 2133 - 2138
(2007/10/03)
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- Pyridopyrimidine analogues as novel adenosine kinase inhibitors
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A novel series of pyridopyrimidine analogues 9 was identified as potent adenosine kinase inhibitors based on the SAR and computational studies. Substitution of the C7 position of the pyridopyrimidino core with C2′ substituted pyridino moiety increased the in vivo potency and enhanced oral bioavailability of these adenosine kinase inhibitors.
- Zheng, Guo Zhu,Lee, Chih-Hung,Pratt, John K.,Perner, Richard J.,Jiang, Mei Qun,Gomtsyan, Arthur,Matulenko, Mark A.,Mao, Yui,Koenig, John R.,Kim, Ki H.,Muchmore, Steve,Yu, Haixia,Kohlhaas, Kathy,Alexander, Karen M.,McGaraughty, Steve,Chu, Katharine L.,Wismer, Carol T.,Mikusa, Joseph,Jarvis, Michael F.,Marsh, Kennan,Kowaluk, Elizabeth A.,Bhagwat, Shripad S.,Stewart, Andrew O.
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p. 2071 - 2074
(2007/10/03)
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