284462-37-9Relevant articles and documents
LEADOPT: An automatic tool for structure-based lead optimization, and its application in structural optimizations of VEGFR2 and SYK inhibitors
Li, Guo-Bo,Ji, Sen,Yang, Ling-Ling,Zhang, Rong-Jie,Chen, Kai,Zhong, Lei,Ma, Shuang,Yang, Sheng-Yong
, p. 523 - 538 (2015)
Lead optimization is one of the key steps in drug discovery, and currently it is carried out mostly based on experiences of medicinal chemists, which often suffers from low efficiency. In silico methods are thought to be useful in improving the efficiency of lead optimization. Here we describe a new in silico automatic tool for structure-based lead optimization, termed LEADOPT. The structural modifications in LEADOPT mainly include two operations: fragment growing and fragment replacing, which are restricted to carry out in the active pocket of target protein with the core scaffold structure of ligand kept unchanged. The bioactivity of the newly generated molecules is estimated by ligand efficiency rather than a commonly used scoring function. Twelve important pharmacokinetic and toxic properties are evaluated using SCADMET, a program for the prediction of pharmacokinetic and toxic properties. LEADOPT was first evaluated using two retrospective cases, in which it showed a very good performance. LEADOPT was then applied to the structural optimizations of the VEGFR2 inhibitor, sorafenib, and the SYK inhibitor, R406. Though just several compounds were synthesized, we have obtained some compounds that are more potent than sorafenib and R406 in enzymatic and functional assays. All of these have validated, at least to some extent, the effectiveness of LEADOPT.
Synthesis and biological evaluation of novel 4-(4-formamidophenylamino)-N-methylpicolinamide derivatives as potential antitumor agents
Hu, Min,Meng, Nana,Xia, Yong,Xu, Youzhi,Yu, Luoting,Zeng, Xiuxiu,Zhou, Shuyan
, (2021/06/11)
A novel series of 4-(4-formamidophenylamino)-N-methylpicolinamide derivatives were synthesized and evaluated against different tumor cell lines. Experiments in vitro showed that these derivatives could inhibit the proliferation of two kinds of human cancer cell lines (HepG2, HCT116) at low micromolar concentrations and the most potent analog 5q possessed broad-spectrum antiproliferative activity. Experiments in vivo demonstrated that 5q could effectively prolong the longevity of colon carcinoma-burdened mice and slow down the progression of cancer cells by suppression of angiogenesis and the induction of apoptosis and necrosis.
Identification of Diarylurea Inhibitors of the Cardiac-Specific Kinase TNNI3K by Designing Selectivity against VEGFR2, p38α, and B-Raf
Cheung, Mui,Desai, Tina A.,Fries, Harvey,Gatto, Gregory J.,Graves, Alan P.,Holt, Dennis A.,Kallander, Lara S.,Patterson, Jaclyn R.,Shewchuk, Lisa,Stoy, Patrick,Totoritis, Rachel,Wang, Liping
, p. 15651 - 15670 (2021/11/16)
A series of diarylurea inhibitors of the cardiac-specific kinase TNNI3K were developed to elucidate the biological function of TNNI3K and evaluate TNNI3K as a therapeutic target for the treatment of cardiovascular diseases. Utilizing a structure-based design, enhancements in kinase selectivity were engineered into the series, capitalizing on the established X-ray crystal structures of TNNI3K, VEGFR2, p38α, and B-Raf. Our efforts culminated in the discovery of an in vivo tool compound 47 (GSK329), which exhibited desirable TNNI3K potency and rat pharmacokinetic properties as well as promising kinase selectivity against VEGFR2 (40-fold), p38α (80-fold), and B-Raf (>200-fold). Compound 47 demonstrated positive cardioprotective outcomes in a mouse model of ischemia/reperfusion cardiac injury, indicating that optimized exemplars from this series, such as 47, are favorable leads for discovering novel medicines for cardiac diseases.
Sorafenib sulfydryl derivative and application thereof
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Paragraph 0019-0021, (2021/04/10)
The invention belongs to the field of medicine, and relates to a sorafenib sulfhydryl derivative and application thereof, in particular to a sorafenib sulfhydryl derivative and application thereof in preparation of an anti-tumor drug targeted delivery carrier. The structure of the sorafenib sulfhydryl derivative is shown as the following formula, a sulfhydryl functional group is introduced into pyridine-2-formamide of an anti-tumor small-molecule targeted drug sorafenib, and sorafenib can be coupled to free amino of polypeptide through proper linker molecules by utilizing the sulfhydryl functional group, so that a sorafenib polypeptide conjugate is constructed, the conjugate can give play to the targeting effect and tumor inhibition effect of sorafenib at the same time, and can be used as a targeting delivery carrier of antitumor drugs.
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
Tan, Ninghua,Wang, Linxiao,Wang, Zhe,Zhang, Qian,Zhu, Wufu
, (2021/07/09)
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.
4 -phenoxypyridine compound containing quinoxalinone and application thereof (by machine translation)
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, (2020/07/13)
The invention belongs to the field of medicines, and particularly relates to 4 -phenoxypyridine compounds containing quinoxalinone and application thereof. The 4 -phenoxypyridine compound containing quinoxalinone has the structure of the general formula (I). The invention also relates to the application of the compound of the general formula (I) to inhibit c-Met kinase and provide 4 -phenoxypyridine compounds containing quinoxalinone and pharmaceutically acceptable salts thereof in preparation of medicines for treating and/or preventing diseases caused by abnormal high expression c-Met kinase. (by machine translation)
Introduction of mercaptoethyl at sorafenib pyridine‐2‐amide motif as a potentially effective chain to further get sorafenib‐PEg‐DGL
Chen, Ying,Kuerbana, Kudelaidi,Wan, Qi,Wang, Ke,Ye, Li,Yu, Zhihui
, (2020/02/11)
The crystal structure of the sorafenib and B‐RAF complex indicates that the binding cavity occupied by the pyridine‐2‐carboxamide in sorafenib has a large variable space, making it a reasonable modification site. In order to identify novel compounds with anti‐cancer activity, better safety and polar groups for further application, five sorafenib analogs with new pyridine‐2‐amide side chains were designed and synthesized. Preliminary pharmacologic studies showed that these compounds displayed much lower toxicities than that of sorafenib. Among them, compound 10b bearing mercaptoethyl group kept relevant antiproliferation potency compared to sorafenib in Huh7 and Hela cell lines with values of IC50 58.79 and 63.67 μM, respectively. As a small molecule inhibitor targeting protein tyrosine kinases, thiol in compound 10b would be an active group to react with maleimide in a mild condition for forming nanoparticles Sorafenib‐PEG‐DGL, which could be developed as a delivery vehicle to improve the concentration of anti‐tumor therapeutic agents in the target cancer tissue and reduce side effects in the next study.
Substituted pyridine-2-formamide compound and application thereof
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Paragraph 0144; 0150-0154, (2020/07/15)
The invention belongs to the technical field of medicinal chemistry, and relates to a substituted pyridine-2-formamide compound and application thereof, wherein specifically the substituted pyridine-2-formamide compound has a structure represented by a formula I. According to the invention, based on excellent in vitro inhibition activity on VEGFR-2 kinase and PDGFR-beta kinase and HUVEC cell inhibition activity, the compound can be used as a small-molecular tyrosine kinase (especially Raf kinase) inhibitor, has the effect of inhibiting cell proliferation and angiogenesis, has good antitumor activity, and has a good effect of treating tumor diseases of mammals (including human beings).
Preparation and application of 2-pyridine carboxamide compound
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Paragraph 0099; 0113-0114, (2019/12/25)
The invention relates to a 2-pyridine carboxamide derivative as shown in a formula I, and pharmaceutically acceptable salt, hydrate, solvate and prodrug thereof. Substituents R1, R2, X and Y have themeanings given in the description. The invention further relates to a compound in the general formula I, and the compound has the strong inhibition effect on FLT-3; the invention further relates to the applications of the compound, and the pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof to preparation of drugs for treating diseases caused by abnormal high expression of FLT-3kinase, especially the applications to preparation of drugs for treating and/or preventing cancers.
Synthesis of deuterium-enriched sorafenib derivatives and evaluation of their biological activities
Zhong, Lili,Hou, Chenhui,Zhang, Liang,Zhao, Jianchun,Li, Feng,Li, Wenbao
, p. 341 - 350 (2018/10/02)
Deuterium substitution has been widely known that can improve the pharmacokinetic profiles due to isotope effect. Herein, a series of deuterated sorafenib derivatives have been synthesized and characterized by 1H NMR, 13C NMR and MS. Their antitumor activities were evaluated in vitro against human hepatoma cell line HepG2 and human cervical carcinoma cell line HeLa. The LogP values were detected by high-performance liquid chromatography. Subsequently, the metabolic stability and pharmacokinetics study were assessed in vitro and in vivo.
