N-[2(S)-(t-Butoxycarbonylamino)-3(S)-methylpentyl]-N-(1-naphthylmethyl)-glycyl-methionine methyl ester | 168539-95-5

• 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: N-[2(S)-(t-Butoxycarbonylamino)-3(S)-methylpentyl]-N-(1-naphthylmethyl)-glycyl-methionine methyl ester
• 英文别名: methyl (2S)-2-[[2-[[(2S,3S)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentyl]-(naphthalen-1-ylmethyl)amino]acetyl]amino]-4-methylsulfanylbutanoate
• CAS: 168539-95-5
• 化学式: C₃₀H₄₅N₃O₅S
• 分子量: 559.77
• InChiKey: UMHXGINMJAFMHK-OUIFVKKZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  39
• 可旋转键数：
  17
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  122
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-[2(S)-(t-Butoxycarbonylamino)-3(S)-methylpentyl]-N-(1-naphthylmethyl)-glycyl-methionine methyl ester 在 盐酸 、 3 A molecular sieve 、 potassium acetate 、 sodium cyanoborohydride 作用下， 以 甲醇 、 乙酸乙酯 为溶剂， 反应 18.0h， 生成 (S)-4-Methylsulfanyl-2-(2-{[(2S,3S)-3-methyl-2-(3-tritylsulfanyl-propylamino)-pentyl]-naphthalen-1-ylmethyl-amino}-acetylamino)-butyric acid methyl ester
  参考文献：
  名称：

  N-Arylalkyl Pseudopeptide Inhibitors of Farnesyltransferase

  摘要：

  Inhibitors of Ras protein farnesyltransferase are described which are reduced pseudopeptides related to the C-terminal tetrapeptide of the Ras protein that signals farnesylation. Reduction of the carbonyl groups linking the first three residues of the tetrapeptide leads to active inhibitors which are chemically unstable. Stability can he restored by alkylating the central amine of the tetrapeptide. Studies of the SAR of these alkylated pseudopeptides with concomitant modification of the side chain of the third residue led to 2(S)-(2(S)-{[2(S)-(2(R)-amino-3-mercaptopropylamino)-3-(S)-methylpentyl]naphthalen-1-ylmethylamino}acetylamino)-4-methylsulfanylbutyric acid (11), a subnanomolar inhibitor. The methyl ester (10) of this compound exhibited submicromolar activity in the processing assay and selectively inhibited anchorage-independent growth of Rat1 cells transformed by v-ras at 2.5-5 mu M.

  DOI：

  10.1021/jm9800907
• 作为产物：
  描述：

  N-(2(S)-(t-butoxycarbonylamino)-3(S)-methylpentyl)glycine methyl ester 在 sodium hydroxide 、 3 A molecular sieve 、 三乙酰氧基硼氢化钠 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三乙胺 作用下， 以 甲醇 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 44.0h， 生成 N-[2(S)-(t-Butoxycarbonylamino)-3(S)-methylpentyl]-N-(1-naphthylmethyl)-glycyl-methionine methyl ester
  参考文献：
  名称：

  N-Arylalkyl Pseudopeptide Inhibitors of Farnesyltransferase

  摘要：

  Inhibitors of Ras protein farnesyltransferase are described which are reduced pseudopeptides related to the C-terminal tetrapeptide of the Ras protein that signals farnesylation. Reduction of the carbonyl groups linking the first three residues of the tetrapeptide leads to active inhibitors which are chemically unstable. Stability can he restored by alkylating the central amine of the tetrapeptide. Studies of the SAR of these alkylated pseudopeptides with concomitant modification of the side chain of the third residue led to 2(S)-(2(S)-{[2(S)-(2(R)-amino-3-mercaptopropylamino)-3-(S)-methylpentyl]naphthalen-1-ylmethylamino}acetylamino)-4-methylsulfanylbutyric acid (11), a subnanomolar inhibitor. The methyl ester (10) of this compound exhibited submicromolar activity in the processing assay and selectively inhibited anchorage-independent growth of Rat1 cells transformed by v-ras at 2.5-5 mu M.

  DOI：

  10.1021/jm9800907

文献信息

• Inhibitors of farnesyl-protein transferase
  申请人：Merck & Co., Inc.

  公开号：US05523456A1

  公开（公告）日：1996-06-04

  The present invention comprises analogs of the CAAX motif of the protein Ras that is modified by farnesylation in vivo. These CAAX analogs inhibit the farnesylation of Ras. Furthermore, these CAAX analogues differ from those previously described as inhibitors of Ras farnesyl transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.

  本发明包括蛋白质Ras的CAAX基序的类似物，在体内通过法尼酰化进行修饰。这些CAAX类似物抑制了Ras的法尼酰化。此外，这些CAAX类似物不同于先前描述的作为Ras法尼酰转移酶抑制剂的类似物，因为它们没有硫醇基团。缺乏硫醇基团在改善动物的药代动力学行为、预防硫醇依赖的化学反应（如快速自氧化和与内源硫醇形成二硫键）以及降低全身毒性方面具有独特优势。本发明还包括含有这些法尼酰转移酶抑制剂的化疗组合物和其生产方法。
• Heterocycle-containing inhibitors of farnesyl-protein transferase
  申请人：Merck & Co., Inc.

  公开号：US05652257A1

  公开（公告）日：1997-07-29

  The present invention comprises analogs of the CAAX motif of the protein Ras that is modified by farnesylation in vivo. These CAAX analogs inhibit the farnesylation of Ras. Furthermore, these CAAX analogues differ from those previously described as inhibitors of Ras farnesyl transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.

  本发明包括蛋白质Ras的CAAX基序的类似物，该基序在体内通过法尼酰化进行修饰。这些CAAX类似物抑制了Ras的法尼酰化。此外，这些CAAX类似物与以前描述的抑制Ras法尼基转移酶的类似物不同，因为它们不具有硫醇基团。缺乏硫醇基团在改善动物体内药代动力学行为、预防硫醇依赖的化学反应（如快速自氧化和与内源硫醇的二硫键形成）以及减少系统毒性方面提供了独特优势。此外，本发明还包括含有这些法尼基转移酶抑制剂的化疗组合物和其生产方法。
• EP0725650A4
  申请人：——

  公开号：EP0725650A4

  公开（公告）日：1999-02-03
• INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
  申请人：MERCK & CO. INC.

  公开号：EP0725650A1

  公开（公告）日：1996-08-14
• EP0783318A4
  申请人：——

  公开号：EP0783318A4

  公开（公告）日：1999-10-20