Stampidine | 217178-62-6

• 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: Stampidine
• 英文别名: N-[p-(4-bromophenyl)-2'3'-didehydro-3'-deoxy-5'-thymidylyl]-L-alanine methyl ester；d4T-5'-[p-bromophenyl methoxyalaninyl phosphate]；methyl (2S)-2-[[(4-bromophenoxy)-[[(2S,5R)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methoxy]phosphoryl]amino]propanoate
• CAS: 217178-62-6
• 化学式: C₂₀H₂₃BrN₃O₈P
• 分子量: 544.296
• InChiKey: VPABMVYNSQRPBD-MIOXLMGNSA-N

物化性质

• 溶解度：
  DMSO：100 mg/mL（183.73 mM；需要超声波）

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  33
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  133
• 氢给体数：
  2
• 氢受体数：
  9

安全信息

• 储存条件：
  存储条件：2-8°C，避免光照，保持干燥并密封。

制备方法与用途

生物活性

Stampidine 是一种核苷逆转录酶抑制剂 (NRTI)，具有高效、广谱的抗 HIV 活性。它能够有效抑制实验室 HIV-1 株 HTLVIIIB (B 包膜亚型) 和主要临床分离株，IC50 值分别为 1 nM 和 2 nM。此外，Stampidine 还可以抑制耐 NRTI 临床分离株和耐 NNRTI 临床分离株，其 IC50 分别为 8.7 nM 和 11.2 nM。

靶点

• IC50: 1 nM (HTLVIIIB), 2 nM (主要临床分离株), 8.7 nM (耐 NRTI 的主要临床分离株), 11.2 nM (耐 NNRTI 的主要临床分离株)

体外研究

• Stampidine（7.8-1,000 μM，作用时间24小时）不会对生殖道上皮细胞产生毒性。
• 在宫颈黏液中，Stampidine 不会影响精子的运动性。

体内研究 体外模型

• 动物模型： SPF 雄性和雌性家猫（体重2.9-6.2 kg），慢性 FIV 感染
• 剂量： 50 mg/kg, 100 mg/kg
• 给药方式： 口服注射
• 结果： 展现出强大的抗逆转录病毒活性。

药代动力学分析

• 动物模型： 雄性比格犬（体重10-12 kg）
• 剂量： 100 mg/kg
• 给药方式： 口服
• 结果： 平均血浆 Cmax 和 AUC 值分别为 15.4 µM 和 23.1 µM·h。平均消除半衰期（t1/2）和平均驻留时间（MRT）分别为 108.6 分钟和 119.4 分钟。

Stampidine 在这些模型中未表现出血细胞减少、贫血、凝血功能障碍或代谢异常等血液学毒性。

反应信息

• 作为反应物：
  描述：

  Stampidine 以 phosphate buffer 、 二甲基亚砜 为溶剂， 反应 20.0h， 生成 [(2S,5R)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methyl phosphate
  参考文献：
  名称：

  Stereospecific chemical and enzymatic stability of phosphoramidate triester prodrugs of d4T in vitro

  摘要：

  The phosphoramidate triester prodrug approach is widely used to deliver nucleotide forms of nucleoside analogues into target cells. We investigated the stereoselective stability of a series of prodrugs of the anti-HIV agent 2',3'-didehydro-2',3'-dideoxythymidine (d4T). Chemical stability was evaluated in phosphate buffer at pH values of biological relevance (i.e. pH 2.0, 4.6, 7.4). Enzymatic stability was tested in human plasma, in Caco-2 cell homogenates and monolayers and in rat liver. The compounds were relatively stable to chemical hydrolysis. Between 50 and 70% of unchanged prodrug was recovered after 16 h incubation in human plasma, with no stereoselective preference for phosphate diastereoisomers. The p-OMe phenyl derivative, however, was an exception and only 5% of one diastereoisomer was recovered. In Caco-2 cells the stability and stereoselectivity largely depended on the experimental conditions: high enzymatic activity and stereoselectivity was observed in cell homogenates, but not in monolayers. In rat liver S9 fractions the stability profile was similar to that in Caco-2 cells and carboxyl ester cleavage appeared to be the sole mechanism of degradation in both media. The large and unpredictable differences in stereoselective metabolic rate of the pronucleotide series here presented suggest that in vivo circulating levels of intact prodrug could exert profoundly different activity or toxicity due to preferential body distribution of one diastereoisomeric form. (C) 2004 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.ejps.2004.02.006
• 作为产物：
  描述：

  司他夫定 在 三乙胺 作用下， 以 1,4-二氧六环 为溶剂， 反应 120.0h， 生成 Stampidine
  参考文献：
  名称：

  Venkatachalam, Taracad K.; Qazi, Sanjive; Uckun, Fatih M., Arzneimittel-Forschung/Drug Research, 2006, vol. 56, # 2 A, p. 152 - 158

  摘要：

  DOI：

文献信息

• Stereochemical influence on lipase-mediated hydrolysis and biological activity of stampidine and other stavudine phosphoramidates
  作者：T.K. Venkatachalam、P. Samuel、F.M. Uckun

  DOI：10.1016/j.bmc.2004.12.024

  日期：2005.3.1

  by lipase-mediated hydrolysis. The target site for the lipase appears to be the methyl ester group of the L-alanine side chain. Accordingly, the D-amino acid substituted isomers Rp or Sp}are resistant to lipase-mediated hydrolysis and exhibit substantially less anti-HIV activity. Molecular modeling results indicate that the L-amino acid configured isomers Rp or Sp} are preferred in the lipase binding

  马丹定和其他卤素取代的司他夫定氨基磷酸酯可通过脂肪酶介导的水解作用活化。脂肪酶的靶位点似乎是L-丙氨酸侧链的甲酯基。因此，D-氨基酸取代的异构体Rp或Sp}对脂肪酶介导的水解具有抗性并且表现出显着较少的抗HIV活性。分子模型结果表明，在脂肪酶结合口袋中，L-氨基酸构型的异构体Rp或Sp}是优选的。
• In Vivo Toxicity, Pharmacokinetics, and Anti-Human Immunodeficiency Virus Activity of Stavudine-5′-(<i>p</i>-Bromophenyl Methoxyalaninyl Phosphate) (Stampidine) in Mice
  作者：Fatih M. Uckun、Sanjive Qazi、Sharon Pendergrass、Elizabeth Lisowski、Barbara Waurzyniak、Chun-Lin Chen、T. K. Venkatachalam

  DOI：10.1128/aac.46.11.3428-3436.2002

  日期：2002.11

  We have evaluated the clinical potential of stavudine-5′-(p-bromophenyl methoxyalaninyl phosphate(stampidine [STAMP]), a novel aryl phosphate derivative of stavudine, as a new anti-human immunodeficiency virus (anti-HIV) agent, by examining its acute, subacute, and chronic toxicity profile in mice as well as by testing its antiviral activity in a surrogate human peripheral blood lymphocyte (Hu-PBL)-SCID mouse model of human AIDS. STAMP was very well tolerated in BALB/c and CD-1 mice, without any detectable acute or subacute toxicity at single intraperitoneal or oral bolus doses as high as 500 mg/kg of body weight. Notably, daily administration of STAMP intraperitoneally or orally for up to 8 consecutive weeks was not associated with any detectable toxicity at cumulative dose levels as high as 6.4 g/kg. Micromolar concentrations of the active STAMP metabolite in plasma were rapidly achieved and maintained for more than 4 h after parenteral as well as oral administration of a nontoxic 100-mg/kg bolus dose of STAMP. In accordance with its favorable pharmacokinetic profile and in vitro potency, STAMP exhibited dose-dependent and potent in vivo anti-HIV activity in Hu-PBL-SCID mice against a genotypically and phenotypically nucleoside analog reverse transcriptase inhibitor (NRTI)-resistant clinical HIV type 1 (HIV-1) isolate (BR/92/019; D67N, L214F, T215D, K219Q) at nontoxic dose levels. The remarkable in vivo safety and potency of STAMP warrants the further development of this promising new antiretroviral agent for possible clinical use in patients harboring NRTI-resistant HIV-1.

  摘要 我们评估了司他夫定-5′-(对溴苯甲氧基丙氨酰磷酸酯(STAMP))作为一种新型抗人类免疫缺陷病毒（抗 HIV）药物的临床潜力，它是司他夫定的一种新型芳基磷酸酯衍生物、通过研究其在小鼠体内的急性、亚急性和慢性毒性概况，以及在人类艾滋病的代用人类外周血淋巴细胞（Hu-PBL）-SCID 小鼠模型中测试其抗病毒活性。BALB/c 和 CD-1 小鼠对 STAMP 的耐受性非常好，单次腹腔注射或口服剂量高达 500 毫克/千克体重时，均未检测到任何急性或亚急性毒性。值得注意的是，连续 8 周每天腹腔注射或口服 STAMP，在累积剂量高达 6.4 克/千克时也未检测到任何毒性。肠外和口服 100 毫克/千克无毒剂量的 STAMP 后，血浆中 STAMP 活性代谢物的微摩尔浓度可迅速达到并维持 4 小时以上。根据其良好的药代动力学特征和体外效力，STAMP 在 Hu-PBL-SCID 小鼠体内对基因型和表型上具有核苷类似物逆转录酶抑制剂（NRTI）抗性的临床 HIV 1 型（HIV-1）分离株（BR/92/019；D67N、L214F、T215D、K219Q）在无毒剂量水平上表现出剂量依赖性和强效的抗 HIV 活性。STAMP 显着的体内安全性和药效使我们有理由进一步开发这种前景广阔的新型抗逆转录病毒药物，以便在临床上用于对 NRTI 耐药的 HIV-1 患者。
• Venkatachalam, Taracad K.; Qazi, Sanjive; Uckun, Fatih M., Arzneimittel-Forschung/Drug Research, 2006, vol. 56, # 2 A, p. 167 - 175
  作者：Venkatachalam, Taracad K.、Qazi, Sanjive、Uckun, Fatih M.

  DOI：——

  日期：——
• Effect of change in nucleoside structure on the activation and antiviral activity of phosphoramidate derivatives
  作者：T.K. Venkatachalam、P. Samuel、S. Qazi、F.M. Uckun

  DOI：10.1016/j.bmc.2005.04.083

  日期：2005.9

  Changing the nucleoside group of a series of phosphoramidate derivatives affects the enzyme mediated hydrolysis rate of the compounds. d4T and AZT-substituted analogs were activated by enzymes such as lipases, esterases, and proteases. On the other hand, 3dT-substituted derivatives were comparatively less prone to hydrolysis under similar experimental conditions. From the experimental results, we propose that-the most preferable nucleoside group for enzyme activation is d4T rather than AZT or 3dT. Additionally, we also observed that depending on the enzymes used the chiral selectivity of the enzymes for the phosphorus center of these phosphoramidate derivatives differed, demonstrating the importance of the nucleoside structure for this class of compounds. (c) 2005 Elsevier Ltd. All rights reserved.
• Enhancing effects of a mono-bromo substitution at the para position of the phenyl moiety on the metabolism and anti-HIV activity of D4T-phenyl methoxyalaninyl phosphate derivatives
  作者：T.K Venkatachalam、Hung-Liang Tai、Rakesh Vig、Chun-Lin Chen、Shyi-Tai Jan、Fatih M Uckun

  DOI：10.1016/s0960-894x(98)00547-2

  日期：1998.11

  d4T-5'-[p-Bromophenyl methoxyalaninyl phosphate] (d4T-pBPMAP), a novel phenyl phosphate derivative of 2',3'-didehydro-2',3'-dideoxythymidine (d4T) that has an enhanced ability to undergo hydrolysis due to the electron withdrawing properties of its single bromo substituent at the para-position of the phenyl moiety, was found to yield substantially more of the key metabolite alaninyl d4T monophosphate (A-d4T-MP) than the unsubstituted d4T-5'-phenyl methoxyalaninyl phosphate or para-methoxy substituted d4T-5'-phenyl methoxydaninyl phosphate. d4T-pBPMAP was tested for its anti-HIV-1 activity in peripheral blood mononuclear cells (PBMNC) and thymidine kinase (TK)-deficient CEM T-cells. d4T-pBPMAP was 12.6-fold more potent than the parent compound d4T in inhibiting p24 production (IC50 values: 44 nM vs 556 nM) and 41.3-fold more potent than d4T in inhibiting the reverse transcriptase (RT) activity (IC50 values: 57 nM vs 2355 nM) in HIV-1-infected TK-deficient CEM cells. Similarly, d4T-pBPMAP was more potent than the unsubstituted or paramethoxy substituted phenyl methoxyalaninyl phosphate derivatives of d4T. d4T-pBPMAP did not exhibit any detectable cytotoxicity to PBMNC or CEM cells at concentrations as high as 10,000 nM. Notably, d4T-pBPMAP was capable of inhibiting the replication of a zidovudine (ZDV/AZT)-resistant HIV-1 strain as well as HIV-2 in PBMNC at nanomolar concentrations. To our knowledge, this is the first demonstration that the potency of the d4T-aryl-phosphate derivatives can be substantially enhanced by introducing a single para-bromo substituent in the aryl moiety. (C) 1998 Published by Elsevier Science Ltd. All rights reserved.