CN103788085B - 2-（喹唑啉-4-氨基）-5-噻唑甲酰胺类衍生物及其生物药物用途 - Google Patents

2-（喹唑啉-4-氨基）-5-噻唑甲酰胺类衍生物及其生物药物用途 Download PDF

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CN103788085B
CN103788085B CN201210426407.1A CN201210426407A CN103788085B CN 103788085 B CN103788085 B CN 103788085B CN 201210426407 A CN201210426407 A CN 201210426407A CN 103788085 B CN103788085 B CN 103788085B
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quinazoline
amino
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thiazole carboxamides
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CN103788085A (zh
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付伟
李变
古险峰
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Fudan University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

本发明属生物制药领域，涉及2‑（喹唑啉‑4‑氨基）‑5‑噻唑甲酰胺类衍生物及其生物药物用途，本发明以高质量的Src受体酪氨酸激酶与其抑制剂saracatinib的复合物晶体结构为基础定义Src活性口袋，并用高速度的虚拟筛选软件DOCK及精确的打分函数搜寻已知化学品库，获得对Src有较高抑制活性的2‑（喹唑啉‑4‑氨基）‑5‑噻唑甲酰胺类小分子化合物。经生物活性测试，结果证实，所述的化合物对Src受体酪氨酸激酶具有较强抑制作用，可制备抗肿瘤药物尤其是因Src激酶信号转导系统调节紊乱而引起的肿瘤药物，及其作为药物先导化合物合成新型Src激酶抑制剂，特别用于治疗与Src相关的肿瘤疾病。

Description

2-（喹唑啉-4-氨基）-5-噻唑甲酰胺类衍生物及其生物药物用途
技术领域
本发明属生物制药领域，涉及2-（喹唑啉-4-氨基）-5-噻唑甲酰胺类衍生物及其生物药物用途，所述的化合物对Src受体酪氨酸激酶具有较强抑制作用，可制备抗肿瘤药物，特别是在治疗与Src相关的肿瘤疾病中的应用。
背景技术
现有技术公开了Src基因其表达产物Src蛋白是一种酪氨酸激酶，该基因是第一个被发现的癌基因，其主要功能为催化下游信号蛋白的酪氨酸残基磷酸化，从而激活信号转导通路。该Src最初被发现存在于Rous肉瘤逆转录病毒（retrovirus Rous sarcoma virus），后续有研究发现细胞中存在与其高度同源的c-Src蛋白激酶。此外，近年来的研究表明Src激酶过表达与人类多种肿瘤的发生于转移有关，如慢性髓样白血病、肺癌、结肠癌、乳腺癌和胰腺癌等（Rosalyn B.Irby and Timothy J.Yeatman,Oncogene(2000)19,5636-5642）。因此，抑制Src的过高酪氨酸激酶活性从而阻断Src介导的肿瘤信号转导通路是一种有潜力的抗肿瘤方法。
于2006年被美国FDA批准上市并用于治疗慢性髓样白血病（CML）的Src小分子抑制，其通用名为dasatinib（由美国百时美施贵宝公司）。此外，已进入临床研究阶段的药物还有bosutinib和saracatinib等。目前，所述的化合物仍存在如下缺陷：如，结构多样性不高，较难以克服肿瘤的耐药性问题等。
基于受体结构的虚拟筛选是目前的一种高效的基于结构的药物设计方法。此方法以计算化学基本原理为基础，高速度的计算机软件及硬件为工具，并结合生物活性测试来快速发现先导化合物，具有低成本、高效率等优点。本发明旨在运用计算机辅助药物设计的方法获得具有新骨架类型的Src激酶抑制剂。
发明内容
本发明的目的是提供新的Src激酶抑制剂，具体涉及2-（喹唑啉-4-氨基）-5-噻唑甲酰胺类衍生物及其生物药物用途，所述的化合物对Src受体酪氨酸激酶具有较强抑制作用，可制备抗肿瘤药物，特别是在治疗与Src相关的肿瘤疾病中的应用。
本发明以高质量的Src受体酪氨酸激酶与其抑制剂saracatinib的复合物晶体结构为基础定义Src活性口袋，并用高速度的虚拟筛选软件DOCK及精确的打分函数搜寻已知化学品库，获得对Src有较高抑制活性的2-（喹唑啉-4-氨基）-5-噻唑甲酰胺类小分子化合物。
本发明所述的化合物具有式I的结构，包括其可用药盐及水合物：
式中
R1：氢、C1-C4烷基、C1-C4取代烷基、苯基、取代苯基、苄基、取代苄基，
R2：氢、卤素、羟基、C1-C4烷氧基、C1-C4磺酰基、氰基、含1-4个碳的酰基，
R3：氢、卤素、羟基、C1-C4烷氧基、C1-C4磺酰基、氰基、含1-4个碳的酰基。
本发明的式I化合物及其药盐或水合物经生物活性测试，结果显示，所述的2-（喹唑啉-4-氨基）-5-噻唑甲酰胺类小分子化合物对Src有较高抑制活性。
进一步，本发明的式I化合物及其药盐或水合物可用于制备抗肿瘤药物。
进一步，本发明的式I化合物可作为先导化合物，进行结构改造，制备和合成新的Src激酶抑制剂。
为了便于理解，以下将通过具体的附图和实施例对本发明进行详细地描述。需要特别指出的是，具体实例和附图仅是为了说明，显然本领域的普通技术人员可以根据本文说明，在本发明的范围内对本发明做出各种各样的修正和改变，这些修正和改变也纳入本发明的范围内。
附图说明
图1为Src激酶晶体结构及其结合口袋（PDB Code：2H8H）。
具体实施方式
实施例1基于DOCK程序和GOLD程序的虚拟筛选
Src激酶的晶体结构取自Protein Data Bank蛋白数据库（PDB Code：2H8H）
，并用Chimera程序对复合物晶体结构预处理，即删除saracatinib和水分子、添加氢原子。Src激酶的活性口袋定义为saracatinib周围以内的空间。
虚拟筛选的主要步骤包括：
1）以GOLD程序筛选已知化学品数据库Enamine，并用打分函数Eint=Evdw+Eelec（Eint：配体-受体相互作用能；Evdw：范德华作用能；Eelec：静电作用能对筛选结果打分；
2）选取打分结果排名前500的化合物；
3）采用GOLD程序中较为精确的打分函数GOLD Score对DOCK的初筛结果重新评估；4）选取GOLD Score大于50的化合物进行后续评估和购买。
实施例2生物活性测试
从Enamine小分子数据库（http://www.asinex.com）中挑选候选化合物，购买并进行活性测试。
挑选的化合物通过Electrophoretic Mobility Shift Assay（EMSA)测试其对Src激酶活性的抑制情况，实验在384孔板上进行。Src激酶抑制剂的阳性对照品为Staurosporine，受试药物和阳性药物均用DMSO溶解并与激酶缓冲液（20mM HEPES,pH 7.5,0.01% Triton X-100,5mM MnCl2,2mM DTT）混合，在振荡器上混合10min，然后将Src激酶加入孔中并于室温条件下孵育10min。将含有酪氨酸的phosphoacceptor peptide FAM-P4和ATP加入孔中，最终得到25uL/孔的酶反应体系，并于28℃孵育60min。孵育结束，没空孔加入25uL终止缓冲液（100mM HEPES,pH 7.5,0.015%Brij-35,0.2%Coating Reagent#3）。用Caliper检测系统读取数据，每浓度测定两副管，每个化合物进行两次独立试验。结果显示，挑选的化合物中，化合物1显示出对Src激酶的高抑制活性，其IC50值1.2uM。
化合物1
结果显示，所述的化合物1对Src激酶具有明显的抑制作用。基于Src激酶与多种肿瘤疾病密切相关，因此，本发明所涉及的化合物可进一步制备抗肿瘤药物，通过抑制Src的过高酪氨酸激酶活性从而阻断Src介导的肿瘤信号转导通路，达到治疗肿瘤的目的；本发明所述的肿瘤包括慢性髓样白血病、肺癌、结肠癌、乳腺癌和胰腺癌等。

Claims (4)

1.如下式的2-(喹唑啉-4-氨基)-5-噻唑甲酰胺类衍生物化合物及其药用盐在制备抗肿瘤药物中的用途；
2.权利要求1所述的2-(喹唑啉-4-氨基)-5-噻唑甲酰胺类衍生物化合物及其药用盐在制备Src激酶抑制剂中的用途。
3.按权利要求1所述的用途，其特征在于，所述的化合物能够抑制Src激酶的活性。
4.按权利要求1所述的用途，其特征在于，所述的肿瘤为与Src相关的肿瘤疾病。
CN201210426407.1A 2012-10-31 2012-10-31 2-（喹唑啉-4-氨基）-5-噻唑甲酰胺类衍生物及其生物药物用途 Expired - Fee Related CN103788085B (zh)

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CN107021960B (zh) * 2017-06-10 2018-07-31 上海普康药业有限公司 一种治疗恶性肿瘤的药物
CN114948961B (zh) * 2022-05-11 2023-09-26 上海傲图智药生物医药有限公司 一种tead小分子抑制剂
CN115677617B (zh) * 2022-11-04 2023-12-26 济南大学 一种靶向c-Src激酶SH3结构域的化合物及其应用

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