4644-61-5Relevant articles and documents
Discovery and optimization of tetrahydropyrido[4,3-d]pyrimidine derivatives as novel ATX and EGFR dual inhibitors
Jing, Tongfei,Miao, Xiuqi,Jiang, Feng,Guo, Ming,Xing, Lingyun,Zhang, Junlong,Zuo, Daiying,Lei, Hongrui,Zhai, Xin
, p. 1784 - 1796 (2018)
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.
Tetrahydropyridine [4,3-d]miazines derivative and purpose thereof
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Paragraph 0134; 0136; 0137, (2018/10/11)
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.
Structural modifications to tetrahydropyridine-3-carboxylate esters en route to the discovery of M5-preferring muscarinic receptor orthosteric antagonists
Zheng, Guangrong,Smith, Andrew M.,Huang, Xiaoqin,Subramanian, Karunai L.,Siripurapu, Kiran B.,Deaciuc, Agripina,Zhan, Chang-Guo,Dwoskin, Linda P.
supporting information, p. 1693 - 1703 (2013/03/29)
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.
