- Discovery of novel akt1 inhibitor induces autophagy associated death in hepatocellular carcinoma cells
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In this study, a series of thieno [2,3-d]pyrimidine derivatives were designed, synthesized and evaluated as novel AKT1 inhibitors. In vitro antitumor assay results showed that compounds 9d-g and 9i potently suppressed the enzymatic activities of AKT1 and
- Yu, Meng,Zeng, Minghui,Pan, Zhaoping,Wu, Fengbo,Guo, Li,He, Gu
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supporting information
(2020/02/03)
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- Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D2 receptor
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We recently described a structurally novel series of negative allosteric modulators (NAMs) of the dopamine D2 receptor (D2R) based on thieno[2,3-d]pyrimidine 1, showing it can be structurally simplified to reveal low molecular weight, fragment-like NAMs that retain robust negative cooperativity, such as 3. Herein, we report the synthesis and functional profiling of analogues of 3, placing specific emphasis on examining secondary and tertiary amino substituents at the 4-position, combined with a range of substituents at the 5/6-positions (e.g. aromatic/aliphatic carbocycles). We identify analogues with diverse pharmacology at the D2R including NAMs with sub-μM affinity (9h) and, surprisingly, low efficacy partial agonists (9d and 9i).
- Fyfe, Tim J.,Kellam, Barrie,Mistry, Shailesh N.,Scammells, Peter J.,Lane, J. Robert,Capuano, Ben
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p. 474 - 490
(2019/03/07)
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- Design, synthesis, biological evaluation and molecular modeling study of new thieno[2,3-d]pyrimidines with anti-proliferative activity on pancreatic cancer cell lines
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Pancreatic cancer is one of the most challenging diseases with seven months only as median survival time due to its poor prognosis. Several enzymes are blamed for the progress of pancreatic cancer especially, platelet-derived growth factor receptors (PDGFRs), this in turn makes them promising targets for its treatment. In this study, twenty eight new compounds based on thieno[2,3-d]pyrimidine scaffold were synthesized as anti-pancreatic cancer agents mimicking the benzofuro[3,2-d]pyrimidine derivative, amuvatinib. Various linkers including amides, esters, ketones, urea and thiourea derivatives were utilized to study their effect on the anti-proliferative activity of these compounds. Most of the tested compounds revealed good cytotoxic activities against pancreatic carcinoma cell line PANC-1. Compound 9d showed the highest cytotoxicity with an IC50 value of 5.4 μM. Furthermore, 9d showed excellent platelet derived growth factor receptor (PDGFR-α) inhibitory activity, with IC50 value 0.155 μM. Docking study was carried out into PDGFR-α active site which showed comparable binding mode to that of FDA approved PDGFR-α inhibitor, imatinib. 3D-Quantitative structure activity relationship (QSAR) model was built up with five-featured pharmacophore which could be implemented for emerging effective lead structures. These compounds could serve as a new chemotype for discovering new agents for pancreatic cancer therapy.
- Salem, Mohamed S.H.,Abdel Aziz, Yasmine M.,Elgawish, Mohamed S.,Said, Mohamed M.,Abouzid, Khaled A.M.
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- Identification of 4-methoxythieno[2,3-d]pyrimidines as FGFR1 inhibitors
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Aim. To identify novel FGFR1 inhibitors using virtual screening approach. Methods. We used methods of organic synthesis, molecular docking via the Autodock 4.2.6 program package and in vitro biochemical tests with γ-32P. Results. In vitro experiments showed that 9 of 23 tested compounds possess inhibitory activity against FGFR1 with IC50 values in the range from 0.9 to 5.6 μM. Conclusions. Nine FGFR1 inhibitors were developed. The mode of compounds binding with the ATP-acceptor site was determined using molecular docking methods and the dependence of the compounds’ activity on the substituents R1, R4 and R5 was evaluated.
- Balanda, A. O.,Bdzhola, V. G.,Kotey, I. M.,Pletnova, L. V.,Protopopov, M. V.,Prykhod’ko, A. O.,Starosyla, S. A.,Yarmoluk, S. M.
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p. 152 - 162
(2020/06/02)
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- Design and synthesis of novel annulated thienopyrimidines as phosphodiesterase 5 (PDE5) inhibitors
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Novel cycloalkene-fused thienopyrimidine analogues with enhanced phosphodiesterase 5 (PDE5) inhibitory properties are presented. The structure of the reported scaffold was modulated through variation of the terminal cycloalkene ring size, as well as by va
- El-Sharkawy, Lina Y.,El-Sakhawy, Rowaida A.,Abdel-Halim, Mohammad,Lee, Kevin,Piazza, Gary A.,Ducho, Christian,Hartmann, Rolf W.,Abadi, Ashraf H.
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- Computer-aided identification, synthesis and evaluation of substituted thienopyrimidines as novel inhibitors of HCV replication
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A structure-based virtual screening technique was applied to the study of the HCV NS3 helicase, with the aim to find novel inhibitors of the HCV replication. A library of ~450000 commercially available compounds was analysed in silico and 21 structures were selected for biological evaluation in the HCV replicon assay. One hit characterized by a substituted thieno-pyrimidine scaffold was found to inhibit the viral replication with an EC50value in the sub-micromolar range and a good selectivity index. Different series of novel thieno-pyrimidine derivatives were designed and synthesised; several new structures showed antiviral activity in the low or sub-micromolar range.
- Bassetto, Marcella,Leyssen, Pieter,Neyts, Johan,Yerukhimovich, Mark M.,Frick, David N.,Brancale, Andrea
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supporting information
p. 31 - 47
(2016/08/01)
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- FLT3 INHIBITORS AND USES THEREOF
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The present invention provides methods of using compounds of formula I: or compositions thereof for the inhibition of FLT3, and the treatment of FLT3-mediated disorders.
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Paragraph 00369-00370; 00569-00570
(2014/12/12)
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- IRAK INHIBITORS AND USES THEREOF
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The present invention relates to compounds and methods useful for inhibiting one or more interleukin-l receptor-associated kinases ("IRAK"). In some embodiments, a provided compound inhibits IRAK-1 and IRAK-4. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.
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Page/Page column 121
(2012/07/28)
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- Convenient and efficient synthesis of some novel fused thieno pyrimidines using gewald's reaction
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Several functionalized thienopyrimidines were synthesized by a facile synthetic method, which includes Gewald's reaction, and were characterized by spectral and analytical data. These functionalized thienopyrimidines were converted to various new chemical
- Nirogi, Ramakrishna V.S.,Kambhampati, Sastri Rama,Kothmirkar, Prabhakar,Arepalli, Sobhanadri,Pamuleti, Narasimha Reddy G.,Shinde, Anil K.,Dubey
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scheme or table
p. 2835 - 2851
(2011/09/12)
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- Design and synthesis of tetrahydropyridothieno[2,3-d]pyrimidine scaffold based epidermal growth factor receptor (EGFR) kinase inhibitors: The role of side chain chirality and michael acceptor group for maximal potency
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HTS hit 7 was modified through hybrid design strategy to introduce a chiral side chain followed by introduction of Michael acceptor group to obtain potent EGFR kinase inhibitors 11 and 19. Both 11 and 19 showed over 3 orders of magnitude enhanced HCC827 a
- Wu, Chia-Hsien,Coumar, Mohane Selvaraj,Chu, Chang-Ying,Lin, Wen-Hsing,Chen, Yi-Rong,Chen, Chiung-Tong,Shiao, Hui-Yi,Rafi, Shaik,Wang, Sing-Yi,Hsu, Hui,Chen, Chun-Hwa,Chang, Chun-Yu,Chang, Teng-Yuan,Lien, Tzu-Wen,Fang, Ming-Yu,Yeh, Kai-Chia,Chen, Ching-Ping,Yeh, Teng-Kuang,Hsieh, Su-Huei,Hsu, John T.-A.,Liao, Chun-Chen,Chao, Yu-Sheng,Hsieh, Hsing-Pang
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scheme or table
p. 7316 - 7326
(2011/02/23)
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- AlCl3-induced (hetero)arylation of thienopyrimidine ring: a new synthesis of 4-substituted thieno[2,3-d]pyrimidines
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AlCl3 facilitated C-C bond forming reaction between 4-chloro-thieno[2,3-d]pyrimidines and (hetero)arenes affording a direct and single-step method for the synthesis of 4-(hetero)aryl substituted thieno[2,3-d]pyrimidines. A number of novel thien
- Kumar, K. Shiva,Chamakuri, Srinivas,Vishweshwar, Peddy,Iqbal, Javed,Pal, Manojit
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supporting information; experimental part
p. 3269 - 3273
(2010/07/18)
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- Synthesis and binding properties of novel selective 5-HT3 receptor ligands
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This work reports on the synthesis and affinities for the 5-HT3 versus the 5-HT4 receptor of new piperazinyl-substituted thienopyrimidine derivatives 20-45 with a view to identify potent and selective ligands for the 5-HT3 receptor. Some of the new compounds show good affinity for the 5-HT3 receptor and, notably, do not display any affinity for the 5-HT4 receptor. 4-(4-Methyl-1-piperazinyl)-2- methylthio-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidine 31 exhibits the highest affinity for the 5-HT3 receptor (Ki=33nM) and behaves as noncompetitive antagonist.
- Modica, Maria,Romeo, Giuseppe,Materia, Luisa,Russo, Filippo,Cagnotto, Alfredo,Mennini, Tiziana,Gaspar, Robert,Falkay, George,Fueloep, Ferenc
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p. 3891 - 3901
(2007/10/03)
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- 4-amino-5,6-substituted thiopheno [2,3-d] pyrimidines, pharmaceutical compositions containing the same, and their use in the treatment or prevention of PDE7B-mediated diseases and conditions
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The invention relates to 4-amino-5,6-substituted thiopheno [2,3-d] pyrimidines, pharmaceutical compositions containing the same and their use to treat or prevent diseases and conditions mediated by the phosphodiesterase enzyme 7B (PDE7B). Diseases and conditions mediated by PDE7B include osteoporosis, osteopenia and asthma.
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