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本文引用的文献

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Angiogenesis: an organizing principle for drug discovery?血管生成：药物发现的一个组织原则？
Nat Rev Drug Discov. 2007 Apr;6(4):273-86. doi: 10.1038/nrd2115.
2
Discovery and development of sorafenib: a multikinase inhibitor for treating cancer.索拉非尼的发现与研发：一种用于治疗癌症的多激酶抑制剂
Nat Rev Drug Discov. 2006 Oct;5(10):835-44. doi: 10.1038/nrd2130.
3
Combining targeted agents: blocking the epidermal growth factor and vascular endothelial growth factor pathways.联合使用靶向药物：阻断表皮生长因子和血管内皮生长因子通路。
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Multiple targeted tyrosine kinase inhibition in the clinic: all for one or one for all?临床中的多重靶向酪氨酸激酶抑制：是齐心协力还是各自为战？
Eur J Cancer. 2006 Jul;42(10):1351-6. doi: 10.1016/j.ejca.2006.02.013. Epub 2006 Jun 5.
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Sunitinib maleate.马来酸舒尼替尼
Nat Rev Drug Discov. 2006 Apr;5(4):279-80. doi: 10.1038/nrd2012.
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Role of tyrosine kinase inhibitors in cancer therapy.酪氨酸激酶抑制剂在癌症治疗中的作用。
J Pharmacol Exp Ther. 2005 Dec;315(3):971-9. doi: 10.1124/jpet.105.084145. Epub 2005 Jul 7.
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Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain.肺腺癌对吉非替尼或厄洛替尼获得性耐药与表皮生长因子受体（EGFR）激酶结构域的二次突变有关。
PLoS Med. 2005 Mar;2(3):e73. doi: 10.1371/journal.pmed.0020073. Epub 2005 Feb 22.
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Optimization of 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor receptor-2 kinase activity.6,7-二取代-4-(芳基氨基)喹啉-3-腈作为人表皮生长因子受体-2激酶活性的口服活性不可逆抑制剂的优化
J Med Chem. 2005 Feb 24;48(4):1107-31. doi: 10.1021/jm040159c.
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Tyrosine kinase inhibitors in cancer therapy.癌症治疗中的酪氨酸激酶抑制剂。
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Antiangiogenic and antitumor agents. Design, synthesis, and evaluation of novel 2-amino-4-(3-bromoanilino)-6-benzylsubstituted pyrrolo[2,3-d]pyrimidines as inhibitors of receptor tyrosine kinases.抗血管生成和抗肿瘤药物。新型2-氨基-4-(3-溴苯胺基)-6-苄基取代吡咯并[2,3-d]嘧啶作为受体酪氨酸激酶抑制剂的设计、合成与评价。
Bioorg Med Chem. 2003 Nov 17;11(23):5155-70. doi: 10.1016/j.bmc.2003.08.034.

N⁴-芳基-6-取代苯基甲基-7H-吡咯并[2,3-d]嘧啶-2,4-二胺作为受体酪氨酸激酶抑制剂。

N⁴-Aryl-6-substitutedphenylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines as receptor tyrosine kinase inhibitors.

机构信息

Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA.

出版信息

Bioorg Med Chem. 2012 Jan 15;20(2):910-4. doi: 10.1016/j.bmc.2011.11.058. Epub 2011 Dec 8.

DOI:10.1016/j.bmc.2011.11.058
PMID:22204741
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3276368/
Abstract

Six novel N(4)-substitutedphenyl-6-substitutedphenylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines were synthesized as multiple receptor tyrosine kinase (RTK) inhibitors and antitumor agents. An improvement in the inhibitory potency against epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor 1 (VEGFR-1) and vascular endothelial growth factor receptor 2 (VEGFR-2) assays and in the A431 cellular proliferation assay was observed for compounds 8-13 over the previously reported 5-7. Three compounds (8, 9 and 13) demonstrated potent, multiple RTK inhibition and were more potent or equipotent compared to the lead compounds 5 and 7 and the standard compounds. Compounds 10 and 12 showed potent inhibition of VEGFR-2 over EGFR, platelet-derived growth factor receptor-β (PDGFR-β) and VEGFR-1. The results indicate that the RTK inhibitory profile could be modulated with slight variations to the N(4)-aryl-6-substitutedphenylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamino scaffold.

摘要

六位新型 N(4)-取代苯基-6-取代苯基甲基-7H-吡咯并[2,3-d]嘧啶-2,4-二胺作为多受体酪氨酸激酶（RTK）抑制剂和抗肿瘤剂被合成。与之前报道的 5-7 相比，化合物 8-13 在表皮生长因子受体（EGFR）、血管内皮生长因子受体 1（VEGFR-1）和血管内皮生长因子受体 2（VEGFR-2）测定中对 EGFR、VEGFR-1 和 VEGFR-2 的抑制活性以及在 A431 细胞增殖测定中均有提高。三种化合物（8、9 和 13）表现出强大的、多 RTK 抑制作用，与先导化合物 5 和 7 以及标准化合物相比，其活性更高或相当。化合物 10 和 12 对 VEGFR-2 的抑制作用强于 EGFR、血小板衍生生长因子受体-β（PDGFR-β）和 VEGFR-1。结果表明，通过对 N(4)-芳基-6-取代苯基甲基-7H-吡咯并[2,3-d]嘧啶-2,4-二氨基支架进行微小的变化，可调节 RTK 抑制谱。