- 4-substituted pyrido [2, 3-d] pyrimidine-7-ketone compound as well as preparation method and application thereof
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The invention discloses 4-substituted pyrido [2, 3-d] pyrimidine-7-ketone compounds with different general formula structures and pharmaceutically acceptable salts, solvates, polymorphic substances, tautomers, metabolites or prodrugs of the 4-substituted pyrido [2, 3-d] pyrimidine-7-ketone compounds. The invention also discloses an effect of the compound as an NEDD8 activating enzyme inhibitor and an application of the compound in preparation of drugs for treating diseases related to NEDD8 activating enzyme abnormality. Pharmacological results show that the compound has good NEDD8 inhibitory activity, tumor cell proliferation resistance and tumor cell apoptosis promotion effects.
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Paragraph 0041-0045
(2021/05/29)
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- Coumarin compounds as well as preparation method and application thereof
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The invention discloses coumarin compounds with different general formula structures and pharmaceutically acceptable salts, solvates, polymorphic substances, tautomers, metabolites or prodrugs thereof. The invention also discloses an effect of the compound as an NEDD8 activating enzyme inhibitor and an application of the compound in preparation of drugs for treating diseases related to NEDD8 activating enzyme abnormality. The invention also discloses an intermediate for preparing the coumarin compound and a preparation method thereof. Pharmacological results show that the compound has high NEDD8 inhibitory activity, tumor cell proliferation resistance and tumor cell apoptosis promotion effects.
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Paragraph 0052-0056
(2021/06/12)
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- Generating Selective Leads for Mer Kinase Inhibitors-Example of a Comprehensive Lead-Generation Strategy
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Mer is a member of the TAM (Tyro3, Axl, Mer) kinase family that has been associated with cancer progression, metastasis, and drug resistance. Their essential function in immune homeostasis has prompted an interest in their role as modulators of antitumor immune response in the tumor microenvironment. Here we illustrate the outcomes of an extensive lead-generation campaign for identification of Mer inhibitors, focusing on the results from concurrent, orthogonal high-throughput screening approaches. Data mining, HT (high-throughput), and DECL (DNA-encoded chemical library) screens offered means to evaluate large numbers of compounds. We discuss campaign strategy and screening outcomes, and exemplify series resulting from prioritization of hits that were identified. Concurrent execution of HT and DECL screening successfully yielded a large number of potent, selective, and novel starting points, covering a range of selectivity profiles across the TAM family members and modes of kinase binding, and offered excellent start points for lead development.
- Nissink, J. Willem M.,Bazzaz, Sana,Blackett, Carolyn,Clark, Matthew A.,Collingwood, Olga,Disch, Jeremy S.,Gikunju, Diana,Goldberg, Kristin,Guilinger, John P.,Hardaker, Elizabeth,Hennessy, Edward J.,Jetson, Rachael,Keefe, Anthony D.,McCoull, William,McMurray, Lindsay,Olszewski, Allison,Overman, Ross,Pflug, Alexander,Preston, Marian,Rawlins, Philip B.,Rivers, Emma,Schimpl, Marianne,Smith, Paul,Truman, Caroline,Underwood, Elizabeth,Warwicker, Juli,Winter-Holt, Jon,Woodcock, Simon,Zhang, Ying
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p. 3165 - 3184
(2021/04/06)
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- HETEROCYCLIC COMPOUNDS AS KINASE INHIBITORS
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Heterocyclic compounds as CDK4 or CDK6 or other CDK inhibitors are provided. The compounds may find use as therapeutic agents for the treatment of diseases and may find particular use in oncology.
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Paragraph 0181; 0295 0600
(2021/01/23)
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- PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONES AS CDK INHIBITORS
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The pyrido[2,3-d]pyrimidin-7(8H)-ones of Formula (1) and pharmaceutical compositions containing compounds of Formula (1) as CDK inhibitors are disclosed herein. Methods and use of a compound of Formula 1 in the treatment of cancer and manufacture are also disclosed.
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Page/Page column 41; 51; 53
(2021/09/17)
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- Structure optimization of positive allosteric modulators of GABAB receptors led to the unexpected discovery of antagonists/potential negative allosteric modulators
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Positive allosteric modulators (PAMs) of GABAB receptor represent an interesting alternative to receptor agonists such as baclofen, as they act on the receptor in a more physiological way and thus are devoid of the side effects typically exerted by the agonists. Based on our interest in the identification of new GABAB receptor PAMs, we followed a merging approach to design new chemotypes starting from selected active compounds, such as GS39783, rac-BHFF, and BHF177, and we ended up with the synthesis of four different classes of compounds. The new compounds were tested alone or in the presence of 10 μM GABA using [35S]GTPγS binding assay to assess their functionality at the receptor. Unexpectedly, a number of them significantly inhibited GABA-stimulated GTPγS binding thus revealing a functional switch with respect to the prototype molecules. Further studies on selected compounds will clarify if they act as negative modulators of the receptor or, instead, as antagonists at the orthosteric binding site.
- Mugnaini, Claudia,Brizzi, Antonella,Mostallino, Rafaela,Castelli, Maria Paola,Corelli, Federico
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- Protection of renal tissues from ischemia through inhibition of the proliferative kinases CDK4 and CDK6
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The presently disclosed subject matter relates to methods and compositions for protecting cells and or tissues from damage due to ischemia. In particular, the presently disclosed subject matter relates to the protective action of cyclin dependent kinase 4/6 (CDK4/6) inhibitors administered to subjects that have been exposed to, or that are at risk of, ischemia.
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Page/Page column 21
(2017/11/27)
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- CYCLIN DEPENDENT KINASE INHIBITORS AND METHODS OF USE
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The presently disclosed subject matter relates to methods and compositions for protecting healthy cells from damage due to DNA damaging agents. In particular, the presently disclosed subject matter relates to the protective action of selective cyclin dependent kinase 4/6 (CDK4/6) inhibitors administered to subjects that have been exposed to or that are at risk of exposure to DNA damage.
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Page/Page column 21
(2016/02/29)
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- Pyrimidine or pyridine pyridine ketone compound and its preparation method and application (by machine translation)
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The invention discloses a kind of type I of the pyrimidine or pyridine pyridine ketone compound and its preparation and application, which belongs to the technical field of pharmaceutical preparation. The compounds have high-efficient and selectively inhibit the cell cycle dependent kinases (Cdks) CDK4 and CDK6 active, and then by inhibiting CDK4/CDK6 prevent tumor cell division. Therefore, the compounds of this invention can be used for CDK4 and CDK6 the involved in cell cycle control disorders result in various diseases, especially suitable for the treatment of malignant tumors. (by machine translation)
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Paragraph 0140; 0150
(2016/10/09)
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- Pyridopyrimidinone derivatives as potent and selective c-jun N-terminal kinase (JNK) inhibitors
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A novel series of 2-aminopyridopyrimidinone based JNK (c-jun N-terminal kinase) inhibitors were discovered and developed. Structure-activity relationships (SARs) were systematically developed utilizing biochemical and cell based assays and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies. Through the optimization of lead compound 1, several potent and selective JNK inhibitors with high oral bioavailability were developed. Inhibitor 13 was a potent JNK3 inhibitor (IC50 = 15 nM), had high selectivity against p38 (IC50 > 10 μM), had high potency in functional cell based assays, and had high stability in human liver microsome (t1/2 = 76 min), a clean CYP-450 inhibition profile, and excellent oral bioavailability (%F = 87). Moreover, cocrystal structures of compounds 13 and 22 in JNK3 were solved at 2.0 ?. These structures elucidated the binding mode (Type-I binding) and can pave the way for further inhibitor design of this pyridopyrimidinone scaffold for JNK inhibition.
- Zheng, Ke,Park, Chul Min,Iqbal, Sarah,Hernandez, Pamela,Park, Hajeung,Lograsso, Philip V.,Feng, Yangbo
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supporting information
p. 413 - 418
(2015/04/27)
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- PYRIMIDINE COMPOUNDS AS KINASE INHIBITORS
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This disclosure relates to compounds, methods for their preparation, pharmaceutical compositions including these compounds and methods for the treatment of cellular proliferative disorders, including, but not limited to, cancer.
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Page/Page column 52; 53; 56
(2014/10/04)
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- Discovery of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7- oxo-7,8-dihydro-pyrido[2,3- d ]pyrimidine-6-carbonitrile (7x) as a potent inhibitor of cyclin-dependent kinase 4 (CDK4) and AMPK-related kinase 5 (ARK5)
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The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multikinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure-activity relationship trends that can be exploited in the design of potent kinase inhibitors. One compound, 8-cyclopentyl-2-[4-(4-methyl- piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6- carbonitrile (7x), was found to be the most active, inducing apoptosis of tumor cells at a concentration of approximately 30-100 nM. In vitro kinase profiling revealed that 7x is a multikinase inhibitor with potent inhibitory activity against the CDK4/CYCLIN D1 and ARK5 kinases. Here, we report the synthesis, structure-activity relationship, kinase inhibitory profile, in vitro cytotoxicity, and in vivo tumor regression studies by this lead compound.
- Reddy, M. V. Ramana,Akula, Balireddy,Cosenza, Stephen C.,Athuluridivakar, Saikrishna,Mallireddigari, Muralidhar R.,Pallela, Venkat R.,Billa, Vinay K.,Subbaiah, D. R. C. Venkata,Bharathi, E. Vijaya,Vasquez-Del Carpio, Rodrigo,Padgaonkar, Amol,Baker, Stacey J.,Reddy, E. Premkumar
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p. 578 - 599
(2014/03/21)
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- Optimization of highly selective 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase
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Optimization of the ADME properties of a series of 2,4-diaminopyrimidine-5- carboxamide inhibitors of Sky kinase resulted in the identification of highly selective compounds with properties suitable for use as in vitro and in vivo tools to probe the effects of Sky inhibition.
- Powell, Noel A.,Hoffman, Jennifer K.,Ciske, Fred L.,Kohrt, Jeffrey T.,Baxi, Sangita M.,Peng, Yun-Wen,Zhong, Min,Catana, Cornel,Ohren, Jeff,Perrin, Lisa A.,Edmunds, Jeremy J.
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p. 1051 - 1055
(2013/03/13)
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- PAK INHIBITORS FOR THE TREATMENT OF CELL PROLIFERATIVE DISORDERS
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Provided herein are PAK inhibitors and methods of utilizing PAK inhibitors for the treatment of cell proliferative disorders and/or CNS disorders.
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Paragraph 0657
(2013/05/21)
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- 2-SUBSTITUTED-8-ALKYL-7-OXO-7,8-DIHYDROPYRIDO[2,3-D] PYRIMIDINE-6-CARBONITRILES AND USES THEREOF
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Compounds according to Formula (I), as well as salts thereof: wherein R1 and R2 are as defined herein, are useful as antiproliferative agents and kinase inhibitors. Synthetic methods for preparing the compounds of Formula (I) are als
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Page/Page column 29
(2012/02/15)
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- Pyrimidinyl pyridone inhibitors of kinases
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This application discloses novel pyrimidinyl pyridone derivatives according to formula I, wherein A, R1, R2, R3, and m are defined as described herein, which inhibit JNK. The compounds disclosed herein are useful to modula
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Page/Page column 39-40
(2009/10/31)
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- PYRIMIDINES AS INHIBITORS OF PHOSPHOINOSITIDE -3-KINASES (PI3K)
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The present invention provides pyrimidines of Formula (I): wherein R4, R6, and Y have any of the values defined therefor in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment
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Page/Page column 43
(2008/06/13)
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- Pyrido[2,3-d]pyrimidin-7-ones as specific inhibitors of cyclin-dependent kinase 4
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Inhibition of the cell cycle kinase, cyclin-dependent kinase-4 (Cdk4), is expected to provide an effective method for the treatment of proliferative diseases such as cancer. The pyrido[2,3-d]-pyrimidin-7-one template has been identified previously as a privileged structure for the inhibition of ATP-dependent kinases, and good potency against Cdks has been reported for representative examples. Obtaining selectivity for individual Cdk enzymes, particularly Cdk4, has been challenging. Here, we report that the introduction of a methyl substituent at the C-5 position of the pyrido[2,3-d]pvrimidin-7-one template is sufficient to confer excellent selectivity for Cdk4 vs other Cdks and representative tyrosine kinases. Further optimization led to the identification of highly potent and selective inhibitors of Cdk4 that exhibit potent antiproliferative activity against human tumor cells in vitro. The most selective Cdk4 inhibitors were evaluated for antitumor activity against MDA-MB-435 human breast carcinoma xenografts in mice.
- VanderWel, Scott N.,Harvey, Patricia J.,McNamara, Dennis J.,Repine, Joseph T.,Keller, Paul R.,Quin III, John,Booth, R. John,Elliott, William L.,Dobrusin, Ellen M.,Fry, David W.,Toogood, Peter L.
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p. 2371 - 2387
(2007/10/03)
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- Pyridopyrimidinone derivatives for treatment of neurodegenerative disease
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This invention provides pyridopyrimidines and 4-aminopyrimidines that are useful for treating cell proliferatives disorders, such as cancer and restenosis. We have now discovered a group of 7,8-dihydro-2 (amino and thio)pyrido[2,3-d]pyrimidines and 2,4-di
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- Pyrido[2,3-D]pyrimidines and 4-aminopyrimidines as inhibitors of cellular proliferation
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This invention provides pyridopyrimidines and 4-aminopyrimidines that are useful for treating cell proliferative disorders, such as cancer and restenosis. We have now discovered a group of 7,8-dihydro-2-(amino and thio)pyrido[2,3-d]pyrimidines and 2,4-dia
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