Structure-guided identification of novel VEGFR-2 kinase inhibitors via solution phase parallel synthesis.

Tripathy R; Reiboldt A; Messina PA; Iqbal M; Singh J; Bacon ER; Angeles TS; Yang SX; Albom MS; Robinson C; Chang H; Ruggeri BA; Mallamo JP

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Structure-guided identification of novel VEGFR-2 kinase inhibitors via solution phase parallel synthesis.

机译：通过溶液相平行合成对新型VEGFR-2激酶抑制剂进行结构指导的鉴定。

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Structural analysis of the essential binding elements of the oxindole-based kinase inhibitor (1) led to the identification of a novel class of heterocyclic-substituted pyrazolones. Knoevenagel condensation of a variety of activated methylene nucleophiles with indole or pyrrole carboxaldehydes provided a focused library of molecules, each containing elements of kinase pharmacophore probe. Initial screening for VEGFR-2 kinase inhibition eliminated several of the probes. Identification of an active pyrazolone motif and further optimization resulted in several highly potent VEGFR-2 inhibitors with cellular efficacy, anti-angiogenic activity ex vivo in rat aortic ring explant cultures, and oral anti-tumor efficacy in nude mice.

机译：对基于羟吲哚的激酶抑制剂（1）的基本结合元件的结构分析导致鉴定出一类新型的杂环取代的吡唑啉酮。各种活化的亚甲基亲核试剂与吲哚或吡咯羧醛的Knoevenagel缩合提供了一个集中的分子库，每个分子都包含激酶药效团探针的元素。最初对VEGFR-2激酶抑制作用的筛选消除了几种探针。活性吡唑啉酮基序的鉴定和进一步优化导致了几种高效的VEGFR-2抑制剂，具有细胞效力，在大鼠主动脉环外植体培养物中的体外抗血管生成活性以及在裸鼠中的口服抗肿瘤功效。

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《Bioorganic and Medicinal Chemistry Letters》 |2006年第8期|共5页
作者
Tripathy R; Reiboldt A; Messina PA; Iqbal M; Singh J; Bacon ER; Angeles TS; Yang SX; Albom MS; Robinson C; Chang H; Ruggeri BA; Mallamo JP;
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正文语种 eng
中图分类药学;生物化学;
关键词
Antineoplastic Agents; Enzyme Inhibitors; Pyrazolones; Vascular Endothelial Growth Factor Receptor-2; 抗肿瘤药; 酶抑制剂;

机译：Antineoplastic Agents;Enzyme Inhibitors;Pyrazolones;Vascular Endothelial Growth Factor Receptor-2;抗肿瘤药;酶抑制剂;

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1. Structure-guided identification of novel VEGFR-2 kinase inhibitors via solution phase parallel synthesis. [J] . Tripathy R, Reiboldt A, Messina PA, Bioorganic and Medicinal Chemistry Letters . 2006,第8期

机译：通过溶液相平行合成对新型VEGFR-2激酶抑制剂进行结构指导的鉴定。
2. Discovery and optimization of 2-aryl oxazolo-pyrimidines as adenosine kinase inhibitors using liquid phase parallel synthesis. [J] . Bauser M, Delapierre G, Hauswald M, Bioorganic and Medicinal Chemistry Letters . 2004,第8期

机译：发现和优化2-芳基恶唑嘧啶作为腺苷激酶抑制剂的液相平行合成。
3. Solution-Phase Parallel Synthesis of Ruxolitinib-Derived Janus Kinase Inhibitors via Copper-Catalyzed Azide-Alkyne Cycloaddition [J] . Gehringer Matthias, Forster Michael, Laufer Stefan A. ACS combinatorial science . 2015,第1期

机译：通过铜 - 催化的叠氮化物 - 炔烃环加成溶液相平行合成Raxolitinib衍生的Janus激酶抑制剂
4. IN SILICO HIT IDENTIFICATION,DRUG REPURPOSING,PHARMACOKINETIC AND TOXICITY PREDICTION OF C-MET KINASE INHIBITORS FOR CANCER THERAPY [C] . Pretisha Flora Cutinho, Venkataramana C.H.S., Suma B.V. Conference on Drug Design and Discovery Technologies . 2020

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5. Part I. Solvolysis regioselectivity and x-ray structure of the duocarmycin SA alkylation subunit. Part II. Solution phase synthesis of compound libraries targeting the erythropoietin receptor. Part III. Identification of a new class of angiogenesis inhibitors which function by blocking the interaction of proteinase MMP2 and integrin alpha(v)beta(3) [D] . Goldberg, Joel Adam 2000

机译：第一部分：杜卡霉素SA烷基化亚基的溶剂分解区域选择性和X射线结构。第二部分靶向促红细胞生成素受体的化合物库的溶液相合成。第三部分通过阻断蛋白酶MMP2和整联蛋白α（v）beta（3）的相互作用来识别新型血管生成抑制剂
6. Experimental Treatment of Estrogen Receptor (ER) Positive Breast Cancer with Tamoxifen and Brivanib Alaninate a VEGFR-2/FGFR-1 Kinase Inhibitor: a potential clinical application of angiogenesis inhibitors [O] . Roshani R Patel, Surojeet Sengupta, Helen R. Kim, -1

机译：雌激素受体（ER）阳性乳腺癌与他莫昔芬和Brivanib丙氨酸一个VEGFR-2 / FGFR-1激酶抑制剂的试验治疗：血管生成抑制剂的潜在临床应用
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8. Solution structure analysis of the conformational changes that occur upon the binding of the protein kinase inhibitor peptide to the catalytic subunit of the cAMP dependent protein kinase [R] . Mitchell, R. D. , Walsh, D. A. , Olah, G. A. , 1994

机译：蛋白激酶抑制剂肽与camp依赖性蛋白激酶催化亚基结合后发生的构象变化的溶液结构分析

Structure-guided identification of novel VEGFR-2 kinase inhibitors via solution phase parallel synthesis.

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