KYS05089 | 955011-81-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: KYS05089
• 英文别名: 2-[N-(5-N',N'-dimethylaminopentyl)-N-methylamino]-3-(4-biphenylyl)-4-methoxycarbonylmethyl-3,4-dihydroquinazoline；Methyl 2-(3-(biphenyl-4-yl)-2-((5-(dimethylamino)pentyl)(methyl)amino)-3,4-dihydroquinazolin-4-yl)acetate；methyl 2-[2-[5-(dimethylamino)pentyl-methylamino]-3-(4-phenylphenyl)-4H-quinazolin-4-yl]acetate
• CAS: 955011-81-1
• 化学式: C₃₁H₃₈N₄O₂
• 分子量: 498.668
• InChiKey: WSNHBKIWKNYYGN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  37
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  48.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  KYS05089 在 盐酸 作用下， 以 水 、 乙酸乙酯 为溶剂， 生成 4-(benzylcarbamoylmethyl)-3-(4-biphenylyl)-2-(N,N′,N′-trimethyl-1,5-pentanediamino)-3,4-dihydroquinazoline hydrochloride
  参考文献：
  名称：

  In vivo evaluation of oral anti-tumoral effect of 3,4-dihydroquinazoline derivative on solid tumor

  摘要：

  An extension of our previously reported 3.4-dihydroquinazoline derivative is investigated. Oral anti-tumoral activity of 3,4-dihydroquinazoline derivative (KYS05090) as potent and selective T-type calcium channel blocker was in vivo evaluated against A549 xenograft in BALB/c(nu/nu) nude mice. The rate of tumor volume increment in mouse model with KY505090-treated group was remarkably slower than that of control group. With respect to tumor weight, it exhibited 60% and 67% tumor growth inhibition through oral administration of 1 and 5 mg/kg of bodyweight, respectively, compared to control and was more potent than paclitaxel (53%). In addition, KYS05090 (10 and 50 mg/kg, po) was found to have a marked analgesic effect in acetic acid-induced writhing test, whereas it did not show any effect on hot plate test. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.11.083
• 作为产物：
  描述：

  2-nitrocinnamic acid 在 硫酸 、 氯化铵 、 三乙胺 、 锌 、 二溴三苯基膦 作用下， 以 甲醇 、 二氯甲烷 、 甲苯 为溶剂， 反应 31.0h， 生成 KYS05089
  参考文献：
  名称：

  3,4-二氢喹唑啉衍生物抑制胆碱酯酶的活性

  摘要：

  体外测试了一系列3,4-二氢喹唑啉衍生物，这些衍生物由我们的化学文库中选自不同化合物的化合物和新合成的化合物组成，分别测试了它们对乙酰胆碱酯酶（AChE，来自鳗鱼）和丁酰胆碱酯酶（BChE，来自马血清）酶。发现大多数化合物显示出弱的AChE和强的BuChE抑制活性。尤其是，化合物8b和8d是该系列产品中针对BChE的最具活性的IC 50对BChE的亲和力值分别为45 nM和62 nM，以及分别高146和161倍。为了了解这些化合物的出色活性，进行了分子对接模拟，以更好地了解3,4-二氢喹唑啉衍生物的结合机理。如我们所料，化合物8b和8d以比AChE更好的相互作用能值与BChE的催化阴离子位点（CAS）和外围位点（PS）结合。此外，两种化合物的非竞争性/混合型抑制作用在动力学研究中进一步证实了它们的双重结合性质。

  DOI：

  10.1016/j.bmcl.2017.01.068

文献信息

• 3,4-DIHYDROQUINAZOLINE DERIVATIVES
  申请人：Lee Jae Yeol

  公开号：US20100120803A1

  公开（公告）日：2010-05-13

  The present invention relates to 3,4-dihydroquinazoline derivatives, a process of preparing them and a pharmaceutical composition including them. The 3,4-dihydroquinazoline derivatives of the present invention have excellent T-type calcium channel blocking effect and anti-cancer activity.

  本发明涉及3,4-二氢喹唑啉衍生物、其制备方法以及包括它们的药物组合物。本发明的3,4-二氢喹唑啉衍生物具有出色的T型钙通道阻滞效果和抗癌活性。
• Discovery of potent T-type calcium channel blocker
  作者：Han Na Seo、Ja Youn Choi、Yun Jeong Choe、Yoonjee Kim、Hyewhon Rhim、So Ha Lee、Jungahn Kim、Dong Jun Joo、Jae Yeol Lee

  DOI：10.1016/j.bmcl.2007.08.070

  日期：2007.11

  The intensive SAR study of 3,.4-dihydroquinazoline series led to the most potent compound 10 (KYS05090: IC50 = 41 +/- 1 nM) against T-type calcium channel and its potency is nearly comparable to that of Kurtoxin. As a small organic molecule, this compound showed the highest blocking activity reported to date. (c) 2007 Elsevier Ltd. All rights reserved.
• In vitro cytotoxicity on human ovarian cancer cells by T-type calcium channel blockers
  作者：Sun Jeong Jang、Heung Woo Choi、Doo Li Choi、Sehyeon Cho、Hong-Kun Rim、Hye-Eun Choi、Ki-Sun Kim、Minghua Huang、Hyewhon Rhim、Kyung-Tae Lee、Jae Yeol Lee

  DOI：10.1016/j.bmcl.2013.10.049

  日期：2013.12

  The growth inhibition of human cancer cells via T-type Ca2+ channel blockade has been well known. Herein, a series of new 3,4-dihydroquinazoline derivatives were synthesized via a brief SAR study on KYS05090 template and evaluated for both T-type Ca2+ channel (Ca(v)3.1) blockade and cytotoxicity on three human ovarian cancer cells (SK-OV-3, A2780 and A2780-T). Most of compounds except 6i generally exhibited more potent cytotoxicity on SK-OV-3 than mibefradil as a positive control regardless of the degree of T-type channel blockade. In particular, eight compounds (KYS05090, 6a and 6c-6h) showing strong channel blockade exhibited almost equal and more potent cytotoxicity on A2780 when compared to mibefradil. On A2780-T paclitaxel-resistant human ovarian carcinoma, two compounds (KYS05090 and 6d) were 20-fold more active than mibefradil. With respect to cell cycle arrest effect on A2780 and A2780-T cells, KYS05090 induced large proportion of sub-G(1) phase in the cell cycle progression of A2780 and A2780-T, meaning the induction of cancer cell death instead of cell cycle arrest via blocking T-type Ca2+ channel. Among new analogues, compounds 6g and 6h induced cell cycle arrest at G(1) phase of A2780 and A2780-T cells in dose-dependent manner and exhibited strong anti-proliferation effects of ovarian cancer cells by blocking T-type Ca2+ channel. Furthermore, 6g and 6h possessing strong cytotoxic effects could induce apoptosis of A2780 cells, which was detected by confocal micrographs using DAPI staining. (C) 2013 Elsevier Ltd. All rights reserved.
• WO2008/136631
  申请人：——

  公开号：——

  公开（公告）日：——
• T-type Ca2+ channel blockers suppress the growth of human cancer cells
  作者：Jae Ho Heo、Han Na Seo、Yun Jeong Choe、Sujin Kim、Chun Rim Oh、Young Deuk Kim、Hyewhon Rhim、Dong Joon Choo、Jungahn Kim、Jae Yeol Lee

  DOI：10.1016/j.bmcl.2008.06.034

  日期：2008.7

  In order to further clarify the role of T-type Ca2+ channels in cell proliferation, we have measured the growth inhibition of human cancer cells by using our potent T-type Ca2+ channel blockers. As a result, KYS05090, a most potent T-type Ca2+ channel blocker, was found to be as potent as doxorubicin against some human cancer cells without acute toxicity. Therefore, this letter provides the biological results that T-type calcium channel is important in regulating the important cellular phenotype transition leading to cell proliferation, and thus novel T-type Ca2+ channel blocker presents new prospects for cancer treatment. (C) 2008 Elsevier Ltd. All rights reserved.