- Design, synthesis, docking, molecular dynamics and bioevaluation studies on novel N-methylpicolinamide and thienopyrimidine derivatives with inhibiting NF-κB and TAK1 activities: Cheminformatics tools RDKit applied in drug design
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Using cheminformatics tools RDKit and literature investigation, four series of 24 thienopyrimidine/N-methylpicolinamide derivatives substituted with pyrimidine were designed, synthesized and evaluated for activities against three cancer cell lines (MDA-MB-231, HCT116 and A549), TAK1 kinase and NF-κB signaling pathway. Almost all compounds showed selectivity toward the A549 cell lines and the most promising compound 38 could inhibit TAK1 kinase and NF-κB signaling pathway with the IC50 values of 0.58 and 0.84 μM. Moreover, 38 can induce cell cycle arrest of A549 cells at the G2/M checkpoint with 30.57% and induce apoptosis (34.94%) in a concentration-dependent manner. And western blot showed that compound 38 could inhibit TNF-α-induced IκBα phosphorylation, IκBα degradation, p65 phosphorylation and TAK1 phosphorylation, and reduce the expression of p65. What's more, the studies of docking, molecular dynamics, MM/PBSA and frequency analysis theoretically supported the conclusions of the bioevaluation.
- Wang, Linxiao,Zhang, Qian,Wang, Zhe,Zhu, Wufu,Tan, Ninghua
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- Design, synthesis and biological evaluation of novel N-sulfonylamidine-based derivatives as c-Met inhibitors via Cu-catalyzed three-component reaction
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In our continuing efforts to develop novel c-Met inhibitors as potential anticancer candidates, a series of new N-sulfonylamidine derivatives were designed, synthesized via Cu-catalyzed multicomponent reaction (MCR) as the key step, and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (A549, HT-29, MKN-45 and MDA-MB-231). Most of the target compounds showed moderate to significant potency at both the enzyme-based and cell-based assay and possessed selectivity for A549 and HT-29 cancer cell lines. The preliminary SAR studies demonstrated that compound 26af (c-Met IC50 = 2.89 nM) was the most promising compound compared with the positive foretinib, which exhibited the remarkable antiproliferative activities, with IC50 values ranging from 0.28 to 0.72 μM. Mechanistic studies of 26af showed the anticancer activity was closely related to the blocking phosphorylation of c-Met, leading to cell cycle arresting at G2/M phase and apoptosis of A549 cells by a concentration-dependent manner. The promising compound 26af was further identified as a relatively selective inhibitor of c-Met kinase, which also possessed an acceptable safety profile and favorable pharmacokinetic properties in BALB/c mouse. The favorable drug-likeness of 26af suggested that N-sulfonylamidines may be used as a promising scaffold for antitumor drug development. Additionally, the docking study and molecular dynamics simulations of 26af revealed a common mode of interaction with the binding site of c-Met. These positive results indicated that compound 26af is a potential anti-cancer candidate for clinical trials, and deserves further development as a selective c-Met inhibitor.
- Fang, Sen-Biao,Li, Hui-Jing,Nan, Xiang,Wu, Rui,Wu, Yan-Chao,Zhang, Jing,Zhang, Zhi-Zhou
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- An improved, scalable synthesis of Notum inhibitor LP-922056 using 1-chloro-1,2-benziodoxol-3-one as a superior electrophilic chlorinating agent
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Background: The carboxylesterase Notum has been shown to act as a key negative regulator of the Wnt signalling pathway by mediating the depalmitoleoylation of Wnt proteins. LP-922056 (1) is an orally active inhibitor of Notum. We are investigating the role of Notum in modulating Wnt signalling in the central nervous system and wished to establish if 1 would serve as a peripherally restricted control. An accessible and improved synthetic route would allow 1 to become more readily available as a chemical tool to explore the fundamental biology of Notum and build target validation to underpin new drug discovery programs. Results: An improved, scalable synthesis of 1 is reported. Key modifications include: (1) the introduction of the C7-cyclopropyl group was most effectively achieved with a Suzuki–Miyaura cross-coupling reaction with MIDA-boronate 11 (5 → 6), and (2) C6 chlorination was performed with 1-chloro-1,2-benziodoxol-3-one (12) (6 → 7) as a mild and selective electrophilic chlorination agent. This 7-step route from 16 has been reliably performed on large scale to produce multigram quantities of 1 in good efficiency and high purity. Pharmacokinetic studies in mouse showed CNS penetration of 1 is very low with a brain/plasma concentration ratio of just 0.01. A small library of amides 17 were prepared from acid 1 to explore if 1 could be modified to deliver a CNS penetrant tool by capping off the acid as an amide. Although significant Notum inhibition activity could be achieved, none of these amides demonstrated the required combination of metabolic stability along with cell permeability without evidence of P-gp mediated efflux. Conclusion: Mouse pharmacokinetic studies demonstrate that 1 is unsuitable for use in models of disease where brain penetration is an essential requirement of the compound but would be an ideal peripherally restricted control. These data will contribute to the understanding of drug levels of 1 to overlay with appropriate in vivo efficacy endpoints, i.e., the PK-PD relationship. The identification of a suitable analogue of 1 (or 17) which combines Notum inhibition with CNS penetration would be a valuable chemical probe for investigating the role of Notum in disease models.
- Willis, Nicky J.,Bayle, Elliott D.,Papageorgiou, George,Steadman, David,Atkinson, Benjamin N.,Mahy, William,Fish, Paul V.
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p. 2790 - 2797
(2019/12/11)
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- Synthesis and bioevaluation study of novel N-methylpicolinamide and thienopyrimidine derivatives as selectivity c-Met kinase inhibitors
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Four series of N-methylpicolinamide moiety and thienopyrimidine moiety bearing pyridazinone were designed and synthesized and evaluated for the IC50 values against three cancer cell lines (A549, HepG2 and MCF-7) and some selected compounds were
- Wang, Linxiao,Xu, Shan,Chen, Xiuying,Liu, Xiaobo,Duan, Yongli,Kong, Dejia,Zhao, Dandan,Zheng, Pengwu,Tang, Qidong,Zhu, Wufu
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p. 245 - 256
(2017/12/06)
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- Synthesis of thienopyrimidine-pyrazolo[3,4-b]pyridine hybrids
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New hybrid compounds, thienopyrimidinyl-1H-pyrazolo[3,4-b]pyridine derivatives, were efficiently synthesized by the three-component reaction of 3-phenyl-1-(thienopyrimidin-4-yl)-1H-pyrazol-5-amine, benzoylacetonitrile and an aromatic aldehyde in the prese
- Park, Jae Woo,Song, Yang-Heon
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p. 281 - 285
(2017/08/15)
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- Evaluation of aromatic 6-substituted thienopyrimidines as scaffolds against parasites that cause trypanosomiasis, leishmaniasis, and malaria
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Target repurposing is a proven method for finding new lead compounds that target Trypanosoma brucei, the causative agent of human African trypanosomiasis. Due to the recent discovery of a lapatinib-derived analog 2 with excellent potency against T. brucei (EC50 = 42 nM) and selectivity over human host cells, we have explored other classes of human tyrosine kinase inhibitor scaffolds in order to expand the range of chemotypes for pursuit. Following library expansion, we found compound 11e to have an EC50 of 84 nM against T. brucei cells while maintaining selectivity over human hepatocytes. In addition, the library was tested against causative agents of Chagas' disease, leishmaniasis, and malaria. Two analogs with sub-micromolar potencies for T. cruzi (4j) and Plasmodium falciparum (11j) were discovered, along with an analog with considerable potency against Leishmania major amastigotes (4e). Besides identifying new and potent protozoan growth inhibitors, these data highlight the value of concurrent screening of a chemical library against different protozoan parasites. This journal is
- Woodring, Jennifer L.,Patel, Gautam,Erath, Jessey,Behera, Ranjan,Lee, Patricia J.,Leed, Susan E.,Rodriguez, Ana,Sciotti, Richard J.,Mensa-Wilmot, Kojo,Pollastri, Michael P.
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p. 339 - 346
(2015/03/30)
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- Protozoan Parasite Growth Inhibitors Discovered by Cross-Screening Yield Potent Scaffolds for Lead Discovery
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Tropical protozoal infections are a significant cause of morbidity and mortality worldwide; four in particular (human African trypanosomiasis (HAT), Chagas disease, cutaneous leishmaniasis, and malaria) have an estimated combined burden of over 87 million disability-adjusted life years. New drugs are needed for each of these diseases. Building on the previous identification of NEU-617 (1) as a potent and nontoxic inhibitor of proliferation for the HAT pathogen (Trypanosoma brucei), we have now tested this class of analogs against other protozoal species: T. cruzi (Chagas disease), Leishmania major (cutaneous leishmaniasis), and Plasmodium falciparum (malaria). Based on hits identified in this screening campaign, we describe the preparation of several replacements for the quinazoline scaffold and report these inhibitors' biological activities against these parasites. In doing this, we have identified several potent proliferation inhibitors for each pathogen, such as 4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-6-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)quinoline-3-carbonitrile (NEU-924, 83) for T. cruzi and N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-7-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)cinnolin-4-amine (NEU-1017, 68) for L. major and P. falciparum.
- Devine, William,Woodring, Jennifer L.,Swaminathan, Uma,Amata, Emanuele,Patel, Gautam,Erath, Jessey,Roncal, Norma E.,Lee, Patricia J.,Leed, Susan E.,Rodriguez, Ana,Mensa-Wilmot, Kojo,Sciotti, Richard J.,Pollastri, Michael P.
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p. 5522 - 5537
(2015/08/03)
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- ANTI-INFLAMMATORY COMPOUND HAVING INHIBITORY ACTIVITY AGAINST MULTIPLE TYROSINE KINASES AND PHARMACEUTICAL COMPOSITION CONTAINING SAME
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The present invention is for the anti-inflammatory compounds that have an inhibitory activity against protein tyrosine kinases and their pharmaceutical composition(s) containing the compound as the active ingredient. Since the compounds of the present invention can inhibit multiple protein kinases associated with inflammatory diseases and immune disorders, they are useful for their prevention or treatment.
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- HETEROARYL COMPOUNDS AND METHODS OF USE THEREOF
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Provided herein are thiophene compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. The compounds provided herein are useful for the treatment, prevention, and/or management of various neurological disorders, including but not limited to, psychosis and schizophrenia.
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Page/Page column 76
(2013/08/28)
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- The efficient one-step chlorination of methylsulfanyl group on pyrimidine ring system with sulfuryl chloride
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A facile one-step transformation of methylsulfanyl and arylsulfanyl groups on pyrimidine ring system into the corresponding chloride group was achieved using sulfuryl chloride in acetonitrile/dichloromethane.
- Ham, Young Jin,Lee, Duck-Hyung,Choi, Hwan Geun,Hah, Jung-Mi,Sim, Taebo
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experimental part
p. 4609 - 4611
(2010/09/18)
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- INDOLYLALKYLTHIENOPYRIMIDYLAMINES AS MODULATORS OF THE EP2 RECEPTOR
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The present invention relates to indolylalkylthienopyhmidylamines of the general formula (I), to processes for their preparation and to their use for production of pharmaceutical compositions for treatment of disorders and indications connected to the EP2
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Page/Page column 31; 34
(2009/03/07)
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- THIENOPYRIMIDYLAMINES AS MODULATORS OF THE EP2 RECEPTOR
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The present invention relates to thienopyrimidylamines of the general formula (I), to processes for their preparation and to their use for production of pharmaceutical compositions for treatment of disorders and indications connected to the EP2
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Page/Page column 32; 35
(2009/03/07)
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- A mild and efficient synthesis of new 3-phenyl-thienotriazolopyrimidine derivatives using iodobenzene diacetate
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New 3-phenylthieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine 9a-i and 3-phenylthieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine 10a-i derivatives were easily synthesized at rt in high yield by the oxidative cyclization of thienopyrimidinyl hydrazones using iodobenzene diacetate.
- Joe, Byeoung Sun,Son, Hoon Young,Song, Yang-Heon
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body text
p. 3091 - 3097
(2009/05/27)
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- A facile synthesis of new 4-(phenylamino)thieno[3,2-d]pyrimidines using 3-aminothiophene-2-carboxamide
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Several new 4-(phenylamino)thieno[3,2-d]pyrimidine derivatives 3 were synthesized in high yield by the reaction of aniline derivatives and 4-chlorothieno[3,2-d]pyrimidine that can be easily prepared using 3-aminothiophene-2-carboxamide.
- Song, Yang-Heon
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- COMPOUND HAVING TGF-BETA INHIBITORY ACTIVITY AND PHARMACEUTICAL COMPOSITION CONTAINING SAME
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The present invention provides compounds of formula (I) or compounds of formula (II) and pharmaceutically acceptable salts or solvates thereof. An objective of the present invention is to provide compounds having TGF2 inhibitory activity.
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Page/Page column 53
(2010/11/24)
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- INHIBITORS OF VEGF RECEPTOR AND HGF RECEPTOR SIGNALING
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The invention relates to the inhibition of vascular endothelial growth factor (VEGF) receptor signaling and hepatocyte growth factor (HGF) receptor signaling. The invention provides compounds and methods for inhibiting VEGF receptor signaling and HGF receptor signaling. The invention also provides compositions and methods for treating cell proliferative diseases and conditions
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Page/Page column 51; 67-68
(2010/02/15)
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- AKT PROTEIN KINASE INHIBITORS
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The present invention provides compounds, including resolved enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof, comprising the Formula: A-L-CR where CR is a cyclical core group, L is a linking group and A is as defined herein. Also provided are methods of using the compounds of this invention as AKT protein kinase inhibitors and for the treatment of hyperproliferative diseases such as cancer.
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- Design and SAR of thienopyrimidine and thienopyridine inhibitors of VEGFR-2 kinase activity
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Novel classes of thienopyrimidines and thienopyridines have been identified as potent inhibitors of VEGFR-2 kinase. The synthesis and SAR of these compounds is presented, along with successful efforts to diminish EGFR activity present in the lead series.
- Munchhof, Michael J.,Beebe, Jean S.,Casavant, Jeffery M.,Cooper, Beth A.,Doty, Jonathan L.,Higdon, R. Carla,Hillerman, Stephen M.,Soderstrom, Catherine I.,Knauth, Elisabeth A.,Marx, Matthew A.,Rossi, Ann Marie K.,Sobolov, Susan B.,Sun, Jianmin
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- Quinazoline derivatives
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The invention concerns quinazoline derivatives of Formula (I) wherein Q1includes a quinazoline ring optionally substituted with a group such as halogeno, trifluoromethyl and cyano, or a group of the formula: Q3—X1— wherein X1includes a direct bond and O and Q3includes aryl, aryl-(1-6C)alkyl, heterocyclyl and heterocyclyl-(1-6C)alkyl; each of R2and R3is hydrogen or (1-6C)alkyl; Z includes O, S and NH; and Q2includes aryl and aryl-(1-3C)alkyl or a pharmaceutically-acceptable salt thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the prevention or treatment of T cell mediated diseases or medical conditions in a warm-blooded animal.
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Page/Page column 86
(2010/02/08)
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- Therapy
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The invention concerns the use of a quinazoline derivative of Formula (I) wherein Q1 includes a quinazoline ring optionally substituted with a group such as halogeno, trifluoromethyl and cyano, or a group of the formula: Q3—X1— wherein X1 includes a direct bond and O and Q3includes aryl, aryl-(1-6C)alkyl, heterocyclyl and heterocyclyl-(1-6C)alkyl; each of R2 and R3 is hydrogen or (1-6C)alkyl; Z includes O, S and NH; and Q2 includes aryl and aryl-(1-3C)alkyl or a pharmaceutically-acceptable salt thereof, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human.
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- Fungicides
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The invention provides the use in combating fungi of compounds of general formula (I) wherein R1is hydrogen, hydroxy, acyl, acyloxy, optionally substituted amino, Ra, Ra3Si, RaS or RaO, whe
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- Thienopyrimidine and thienopyridine derivatives useful as anticancer agents
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The invention relates to compounds of the formulas 1 and 2 and to pharmaceutically acceptable salts and hydrates thereof, wherein X1, R1, R2and R11are as defined herein. The invention also relates to pharmaceutical compositions containing the compounds of formulas 1 and 2 and to methods of treating hyperproliferative disorders in a mammal by administering the compounds of formulas 1 and 2.
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- Design, synthesis, and biological activities of new thieno[3,2- d]pyrimidines as selective type 4 phosphodiesterase inhibitors
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A common pharmacophore for compounds structurally related to nitraquazone has been derived. Using this pharmacophore, new structures have been designed, synthesized, and evaluated for their inhibitory potencies against cyclic adenosine 5'-monophosphate (c
- Crespo, Maria I.,Pagès, Lluís,Vega, Armando,Segarra, Victor,López, Manel,Doménech, Teresa,Miralpeix, Montserrat,Beleta, Jordi,Ryder, Hamish,Palacios, José M.
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p. 4021 - 4035
(2007/10/03)
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- Thienopyrimidine derivatives
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4-Substituted-thieno[2,3-d], [3,2-d], and [3,4-d]pyrimidines having fungicidal, insecticidal, and miticidal utility are disclosed. Related 3-substituted-thieno[2,3-d], [3,2-d], and [3,4-d]pyrimidin-4-(3H)-imines are useful as fungicides, insecticides, and
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