2(S)-<2-[(2(S)-<2-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]acetylamino>-3(S)-methylpentyl)naphthalen-1-ylmethylamino]acetylamino>-4-(methylsulfanyl)butyric acid methyl ester | 179026-12-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 2(S)-<2-[(2(S)-<2-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]acetylamino>-3(S)-methylpentyl)naphthalen-1-ylmethylamino]acetylamino>-4-(methylsulfanyl)butyric acid methyl ester
• 英文别名: methyl (2S)-2-[[2-[[(2S,3S)-2-[[2-[3-[(4-cyanophenyl)methyl]imidazol-4-yl]acetyl]amino]-3-methylpentyl]-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate
• CAS: 179026-12-1
• 化学式: C₃₈H₄₆N₆O₄S
• 分子量: 682.887
• InChiKey: HQFUINJGHRJKJL-DPGDXNODSA-N

物化性质

• 沸点：
  925.9±65.0 °C(Predicted)
• 密度：
  1.19±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  49
• 可旋转键数：
  19
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  155
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2(S)-<2-[(2(S)-<2-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]acetylamino>-3(S)-methylpentyl)naphthalen-1-ylmethylamino]acetylamino>-4-(methylsulfanyl)butyric acid methyl ester 在 sodium hydroxide 作用下， 以 乙醇 为溶剂， 反应 2.0h， 生成 2(S)-<2-[(2(S)-<2-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]acetylamino>-3(S)-methylpentyl)naphthalen-1-ylmethylamino]acetylamino>-4-(methylsulfanyl)butyric acid
  参考文献：
  名称：

  Design and in Vivo Analysis of Potent Non-Thiol Inhibitors of Farnesyl Protein Transferase

  摘要：

  Inhibitors of farnesyl protein transferase (FPTase) based upon a pseudotripeptide template are described that comprise an imidazole group substituted with a hydrophobic substituent. (1,5)-Disubstitution of the imidazole group is shown to be the optimal array that leads to potent and selective inhibitors of FPTase. A variety of aryl and isoprenyl substituents are shown to afford effective inhibitors, and the mechanism by which these compounds inhibit FPTase has been investigated. The biochemical. behavior of these compounds suggests that they bind to FPTase at the site usually occupied by the protein substrate. In experiments in cell culture, the methyl ester prodrugs of these inhibitors are cell permeant and potently inhibit the posttranslational modification of H-Ras protein. Additionally, these molecules revert the phenotype of ras transformed cells as evidenced by their ability to slow the growth of ras transformed cell lines in soft agar. One of the inhibitors, as its methyl prodrug, was evaluated in two in vivo models of tumor growth. The compound selectively inhibited the growth of tumors derived from H-ras transformed cells, in nude mice, and caused the regression of preexisting tumors in an H-ras transgenic animal model.

  DOI：

  10.1021/jm990080l
• 作为产物：
  描述：

  甲基(1-trityl-1H-imidazol-4-yl)乙酸酯 在 甲醇 、 lithium hydroxide 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三乙胺 、 3-羟基-1,2,3-苯并三嗪-4(3H)-酮 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 50.5h， 生成 2(S)-<2-[(2(S)-<2-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]acetylamino>-3(S)-methylpentyl)naphthalen-1-ylmethylamino]acetylamino>-4-(methylsulfanyl)butyric acid methyl ester
  参考文献：
  名称：

  Design and in Vivo Analysis of Potent Non-Thiol Inhibitors of Farnesyl Protein Transferase

  摘要：

  Inhibitors of farnesyl protein transferase (FPTase) based upon a pseudotripeptide template are described that comprise an imidazole group substituted with a hydrophobic substituent. (1,5)-Disubstitution of the imidazole group is shown to be the optimal array that leads to potent and selective inhibitors of FPTase. A variety of aryl and isoprenyl substituents are shown to afford effective inhibitors, and the mechanism by which these compounds inhibit FPTase has been investigated. The biochemical. behavior of these compounds suggests that they bind to FPTase at the site usually occupied by the protein substrate. In experiments in cell culture, the methyl ester prodrugs of these inhibitors are cell permeant and potently inhibit the posttranslational modification of H-Ras protein. Additionally, these molecules revert the phenotype of ras transformed cells as evidenced by their ability to slow the growth of ras transformed cell lines in soft agar. One of the inhibitors, as its methyl prodrug, was evaluated in two in vivo models of tumor growth. The compound selectively inhibited the growth of tumors derived from H-ras transformed cells, in nude mice, and caused the regression of preexisting tumors in an H-ras transgenic animal model.

  DOI：

  10.1021/jm990080l

文献信息

• 癌の治療方法
  申请人：メルク エンド カムパニー インコーポレーテッド

  公开号：JP2001518281A

  公开（公告）日：2001-10-16

  \n (57)【要約】\n本発明は、ゲラニルゲラニル−プロテイントランスフェラーゼＩ型（ＧＧＴａｓｅ−Ｉ）の阻害剤としてイン・ビボで効果的なプレニル−プロテイントランスフェラーゼ阻害剤を哺乳動物に投与することを含んでなる、プレニル−プロテイントランスフェラーゼを阻害し癌を治療する方法を提供する。本発明は、ファルネシル−プロテイントランスフェラーゼおよびゲラニルゲラニル−プロテイントランスフェラーゼＩ型をこれらのプレニル−プロテイントランスフェラーゼの両方の二重阻害剤である化合物を投与することにより阻害する方法も提供する。本発明は、上記の様な化合物を同定する方法であって、該方法はプレニル−プロテイントランスフェラーゼのイン・ビトロでの効力をそのイン・ビボでの効力が予測できる様に変化させる調整アニオンを組み込んだ修飾された阻害剤アッセイを含んでなり、それ故にイン・ビボにおいて上記の様な活性を有する化合物を効率よく固定可能な方法をも提供する。\n

  一种抑制前酰-蛋白转移酶和治疗癌症的方法，包括给动物用药。本发明提供了一种抑制法尼基-蛋白转移酶和geranylgeranyl-蛋白转移酶 I 型的方法，其方法是施用一种对这两种前酰-蛋白转移酶都是双重抑制剂的化合物。本发明还提供了通过施用对这两种前酰-蛋白转移酶具有双重抑制作用的化合物进行抑制的方法。本发明还提供了一种鉴定上述化合物的方法，该方法包括一种改良的抑制剂测定法，其中加入了一种量身定做的阴离子，该阴离子可改变前烯醇-蛋白转移酶的体外效力，从而可预测其体内效力，并因此因此，它还提供了一种可以在体内有效固定具有上述活性的化合物的方法。\n
• THIOL-FREE INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
  申请人：Merck & Co., Inc.

  公开号：EP0783517A2

  公开（公告）日：1997-07-16
• A METHOD OF TREATING CANCER
  申请人：MERCK & CO., INC.

  公开号：EP1009854A1

  公开（公告）日：2000-06-21
• EP1019529A4
  申请人：——

  公开号：EP1019529A4

  公开（公告）日：2002-09-11
• US5652257A
  申请人：——

  公开号：US5652257A

  公开（公告）日：1997-07-29