KYS0590

• 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: KYS0590
• 英文别名: BK10001；KYS 05090；4-(N-benzylacetamino)-3-(biphenyl-4-yl)-2-N'-(5-N'',N''-dimethylaminopentyl)-N'-methylamino-3,4-dihydroquinazoline；4-(N-benzylacetamino)-3-(4-biphenylyl)-2-[N-(5-N',N'-dimethylaminopentyl)-N-methylamino]-3,4-dihydroquinazoline；N-benzyl-2-(3-(biphenyl-4-yl)-2-((5-(dimethylamino)pentyl)(methyl)amino)-3,4-dihydroquinazolin-4-yl)acetamide；N-benzyl-2-[2-[5-(dimethylamino)pentyl-methylamino]-3-(4-phenylphenyl)-4H-quinazolin-4-yl]acetamide
• 化学式: C₃₇H₄₃N₅O
• 分子量: 573.781
• InChiKey: QVXCZTNUVKNCGU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  43
• 可旋转键数：
  13
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  51.2
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  KYS0590 在 盐酸 作用下， 以 水 、 乙酸乙酯 为溶剂， 以99%的产率得到4-(benzylcarbamoylmethyl)-3-(4-biphenylyl)-2-(N,N′,N′-trimethyl-1,5-pentanediamino)-3,4-dihydroquinazoline hydrochloride
  参考文献：
  名称：

  Antitumor activity of 3,4-dihydroquinazoline dihydrochloride in A549 xenograft nude mice

  摘要：

  In the previous article we have reported that 3,4-dihydroquinazoline 1 is a potent and selective T-type calcium channel blocker that exhibited strong anti-cancer activity in vitro. Compound 1 center dot 2HCl was further in vivo evaluated against A549 xenograft in BALB/c nude mice, which exhibited 49% tumor-weight inhibition through intravenous administration of 2 mg/kg of body weight and was more potent than doxorubicin. Moreover, compound 1 center dot 2HCl has an oral bioavailability of 98% with LD(50) values of 693 mg/kg (po route) and 40.0 mg/kg (iv route) of body weight. In addition, its efficient scale-up synthetic method was developed. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.09.020
• 作为产物：
  描述：

  2-nitrocinnamic acid 在 硫酸 、 1,5,7-三氮杂双环[4.4.0]癸-5-烯 、 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 43.0h， 生成 KYS0590
  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

• Anti-Cancer Activity of T-Type Calcium Channel Blocker In Vivo
  作者：Hang-Ah Park、Soo-Yeon Jung、So-Hyung Lee、Han-Byul Kang、Min-Sik Min、Jung-Ahn Kim、Dong-Joon Choo、Chun-Rim Oh、Young-Deuk Kim、Kyung-Tae Lee、Jae-Yeol Lee

  DOI：10.5012/bkcs.2010.31.11.3353

  日期：2010.11.20

  3,4-Dihydroquinazoline 1 as T-type calcium channel blocker was in vivo evaluated against A549 xenograft in BALB/c-nu Slc mice, which exhibited 54% tumor growth inhibition through oral administration of 8 mg/kg of body weight and was slightly less active than doxorubicin (68%). In addition, this compound was also profiled for its acute toxicity to ICR mice to afford oral $LD_50}$ value of 1,038 mg/kg of body weight.

  3,4-二氢喹唉1作为T型钙通道阻滞剂，在BALB/c-nu Slc裸鼠的A549异种移植模型中进行了体内评估，口服给药8毫克/千克体重显示出54%的肿瘤生长抑制作用，略低于多柔比星的68%活性。此外，还对该化合物对ICR小鼠的急性毒性进行了评估，得到了口服LD50值为1038毫克/千克体重。
• Synthesis and SAR Study of T-Type Calcium Channel Blockers. Part II
  作者：Yun Jeong Choe、Han Na Seo、Soo Yeon Jung、Hyewhon Rhim、Jungahn Kim、Dong Joon Choo、Jae Yeol Lee

  DOI：10.1002/ardp.200800079

  日期：2008.10

  3,4‐Dihydroquinazoline derivatives have been known to be the novel and potent T‐type calcium channel blockers. From a systematic variation of 3,4‐dihydroquinazoline derivative 5c (KYS05043), plausible SAR results were established. It was revealed that a 5‐(dimethylamino)pentylamino group at R1, a biphenyl group at R2, and a benzyl amido group at R3 in the 3,4‐dihydroquinazoline backbone are closely

  已知 3,4-二氢喹唑啉衍生物是新型有效的 T 型钙通道阻滞剂。根据 3,4-二氢喹唑啉衍生物 5c (KYS05043) 的系统变异，建立了合理的 SAR 结果。结果表明，3,4-二氢喹唑啉骨架中R1的5-(二甲氨基)戊氨基、R2的联苯基和R3的苄基氨基与通道选择性(T/N型)密切相关。以及基于 6k (KYS05090) 发现的效力。
• 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 vivo evaluation of oral anti-tumoral effect of 3,4-dihydroquinazoline derivative on solid tumor
  作者：Han Byul Kang、Hong-Kun Rim、Jin Yeong Park、Heung Woo Choi、Doo Li Choi、Ji-Hyung Seo、Kyung-Sook Chung、Geun Huh、Jungahn Kim、Dong Joon Choo、Kyung-Tae Lee、Jae Yeol Lee

  DOI：10.1016/j.bmcl.2011.11.083

  日期：2012.1

  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.