- Discovery and optimization of tetrahydropyrido[4,3-d]pyrimidine derivatives as novel ATX and EGFR dual inhibitors
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In order to discovery autotaxin (ATX) and EGFR dual inhibitors with potential therapeutic effect on IPF-LC, a series of novel tetrahydropyrido[4,3-d]pyrimidine derivatives possessing semicarbazones moiety were designed and synthesized. The preliminary investigation at the cellular level indicated six compounds (7h, 8a, 8c, 8d, 9a and 9d) displayed preferable anti-tumor activities against A549, H1975, MKN-45 and SGC cancer cells. Further enzymatic assay against EGFR kinase identified 8a and 9a as promising hits with IC50 values of 18.0 nM and 24.2 nM. Meanwhile, anti-inflammatory assessment against cardiac fibroblasts (CFs) cell and RAW264.7 macrophages led to the discovery of candidate 9a, which exhibited considerable potency both on inhibition rate of 77% towards CFs and on reducing NO production to 1.05 μM at 10 μg/mL. Simultaneously, 9a indicated preferable potency towards ATX with IC50 value of 29.1 nM. Significantly, a RT-PCR study revealed the function of 9a to down-regulate the mRNA expression of TGF-β and TNF-α in a dose-dependent manner. The molecular docking analysis together with the pharmacological studies validated 9a as a potential ATX and EGFR dual inhibitor for IPF-LC treatments.
- Jing, Tongfei,Miao, Xiuqi,Jiang, Feng,Guo, Ming,Xing, Lingyun,Zhang, Junlong,Zuo, Daiying,Lei, Hongrui,Zhai, Xin
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- Synthesis and antitumor evaluation of novel 4-anilino-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate derivatives as potential EGFR inhibitors
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Novel series of 4-anilino-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylates (5a–p, 7, and 8a–e) were synthesized and evaluated for their antiproliferative activity against the A549, HT29, H460, and H1975 cancer cell lines in vitro. Nine compounds (5a–c, 5i, 5j, 7, 8a, 8b, 8i) demonstrated moderate to significant cytotoxic activity with IC50 values below 18 μM on A549 cells, which were comparable to that of the reference gefitinib (IC50 = 18.44 μM). Especially, the further enzymatic analysis on epidermal growth factor receptor (EGFR), HER2, and VEGFR identified compound 5a as a promising hit that exhibited considerable potency both in cellular (IC50 = 5.67, 17.04, 11.29, and 12.65 μM, respectively) and EGFR enzymatic assays (IC50 = 14.8 nM). Compound 5a was capable of down-regulating the expression of EGFR and inhibited EGFR phosphorylation in a dose-dependent manner, representing a potential EGFR candidate for further optimization.
- Zhang, Dajun,Yan, Yan,Jin, Ge,Liu, Bo,Ma, Xiaoliang,Han, Dan,Jia, Xiaojian
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- Tetrahydropyridine [4,3-d]miazines derivative and purpose thereof
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The invention relates to a tetrahydropyridine [4,3-d]miazines derivative and an optical isomer shown as a general formula I, pharmaceutically acceptable salt, a solvate or a prodrug, preparation methods thereof, and a pharmaceutical composition taking a compound shown as a general formula I as an active component, wherein substituent R1, R3, L, and P have meanings in the specification. The invention relates to the compound shown in the general formula I having strong ATX and EGFR kinases inhibition effect, the invention also relates to the compound and the optical isomer, and the application of the pharmaceutically acceptable salt for preparing a medicine for treating and/or preventing disease caused by ATX and EGFR abnormal expression, and especially relates to the purpose of the compoundin preparation of the medicine for treating and/or preventing fibration and cancer.
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Paragraph 0134; 0136; 0137
(2018/10/11)
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- Discovery of a novel class anti-proliferative agents and potential inhibitors of EGFR tyrosine kinases based on 4-anilinotetrahydropyrido[4,3-d]pyrimidine scaffold: Design, synthesis and biological evaluations
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A novel series of 4-arylamino-6/7-substituted-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines were designed, synthesized and their biological activities as the potential anti-proliferative agents and EGFR kinase inhibitors were evaluated. Both of N-acrylamide fragment in THPPs and 4-aniline groups with substituents played key roles for their significant anti-proliferative activities against four cancer cell lines (HT29, A549, H460 and H1975). Especially inhibitory activity of Gefitinib-resistant H1975 were showed more favorable, which could be observed from compounds 13b, 13c, 13n, 13o, 13p, 13r, 13s, 13u and 24c obviously. By evaluation of inhibiting EGFR and HER2 kinases, seven compounds (13b, 13g, 13n, 13o, 13p, 13r and 13s) showed stronger EGFR potency with IC50 ≤ 18 nM, which could also be understood by preliminary docking study of 13b with EGFR kinase. In view of the primary SAR, bisarylaniline derivatives (13o, 13p, 13r and 13s) showed obvious improvements on HER2 inhibition, which indicated their being potential EGFR/HER2 dual kinase inhibitors.
- Zhang, Yong,Zhang, Kai,Zhao, Meng,Zhang, Lixia,Qin, Mingze,Guo, Shuchun,Zhao, Yanfang,Gong, Ping
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p. 4591 - 4607
(2015/08/03)
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- Structural modifications to tetrahydropyridine-3-carboxylate esters en route to the discovery of M5-preferring muscarinic receptor orthosteric antagonists
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The M5 muscarinic acetylcholine receptor is suggested to be a potential pharmacotherapeutic target for the treatment of drug abuse. We describe herein the discovery of a series of M5-preferring orthosteric antagonists based on the scaffold of 1,2,5,6-tetrahydropyridine-3- carboxylic acid. Compound 56, the most selective compound in this series, possesses an 11-fold selectivity for the M5 over M1 receptor and shows little activity at M2-M4. This compound, although exhibiting modest affinity (Ki = 2.24 μM) for the [3H]N-methylscopolamine binding site on the M5 receptor, is potent (IC50 = 0.45 nM) in inhibiting oxotremorine-evoked [3H]DA release from rat striatal slices. Further, a homology model of human M5 receptor based on the crystal structure of the rat M3 receptor was constructed, and docking studies of compounds 28 and 56 were performed in an attempt to understand the possible binding mode of these novel analogues to the receptor.
- Zheng, Guangrong,Smith, Andrew M.,Huang, Xiaoqin,Subramanian, Karunai L.,Siripurapu, Kiran B.,Deaciuc, Agripina,Zhan, Chang-Guo,Dwoskin, Linda P.
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supporting information
p. 1693 - 1703
(2013/03/29)
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- Amine-mediated tandem conjugative isomerization-bridging Michael addition: Concise synthesis of 1-azabicyclo[3.3.1]nonanes
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To reach densely functionalized 1-azabicyclo[3.3.1]nonane frameworks synthesis, a stereocontrolled bridging Michael addition involving an unexplored C-5/C-6 disconnection strategy was studied. 1-Azabicyclo[3.3.1]nonane scaffolds have been diastereoselectively elaborated in fairly good yields by two concise pathways implying pyrrolidine derivative organocatalyst or enantiopure 1-phenylethylamine.
- Ngo, Anh Ngoc,El Kassimi, Khadija,Amara, Zacharias,Drège, Emmanuelle,Joseph, Delphine
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supporting information; experimental part
p. 3296 - 3300
(2012/08/08)
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- Enzyme-catalyzed kinetic resolution of piperidine hydroxy esters
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Enantiomers of N-protected piperidine-based cis- and trans-4-hydroxy-3- carboxylates and cis-3-hydroxy-4-carboxylates were prepared through kinetic resolution utilizing lipase AK from Pseudomonas fluorescens and Candida antarctica lipase A. The highly enantioselective (E >200) kinetic resolution of (±)-ethyl cis-(±)-4 and trans-1-(tert-butoxycarbonyl)-4- hydroxypiperidine-3-carboxylate (±)-5 was achieved by Pseudomonas fluorescens lipase-catalyzed asymmetric acylation with vinyl acetate in diisopropyl ether at room temperature. Candida antarctica lipase A-catalyzed asymmetric acylation of (±)-ethyl cis-1-benzyl-3-hydroxypiperidine-4- carboxylate (±)-11 was performed with vinyl propanoate in diisopropyl ether at 3°C, with good enantioselectivity (E = 75).
- Solymar, Magdolna,Forro, Eniko,Fueloep, Ferenc
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p. 3281 - 3287
(2007/10/03)
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- Indoles
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A 1,4-substituted cyclic amine derivative represented by the following formula or a pharmacologically acceptable salt thereof: wherein A, B, C, D, T, Y, and Z each represent a methine or a nitrogen linkage; R1, R2, R3, R4, and R5 each represent a substituent; n represents 0 or an integer of 1 to 3; m represents 0 or an integer of 1 to 6; and p represents an integer of 1 to 3. The compounds have serotonin antagonism. They are therefore clinically useful as medicaments, in particular, for treating, ameliorating, and preventing spastic paralysis. They are also useful as central muscle relaxants for ameliorating myotonia.
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- Palladium-catalyzed allylation of 3-hydroxyisoxazole, 5-isoxazolone and 5-pyrazolone systems
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Kinetic vs. thermodynamic control and steric hindrance are factors that determine the regioselectivity of the Pd(O)-catalyzed allylation of ambident heterocycles of the 3-hydroxyisoxazole, 5-isoxazolone and 5-pyrazolone series.
- Moreno-Manas, Marcial,Perez, Montserrat,Pleixats, Roser
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p. 515 - 528
(2007/10/02)
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