5-[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]-N-(2-pyrrolidin-1-ylethyl)pentanamide | 1415397-35-1

• 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: 5-[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]-N-(2-pyrrolidin-1-ylethyl)pentanamide
• CAS: 1415397-35-1
• 化学式: C₂₁H₂₉N₅O₂S
• 分子量: 415.56
• InChiKey: UPLGSCROHQZZQN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  29
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  116
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  5-(5-amino-1,3,4-thiadiazol-2-yl)pentanoic acid 在 三乙胺 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 72.17h， 生成 5-[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]-N-(2-pyrrolidin-1-ylethyl)pentanamide
  参考文献：
  名称：

  Design, Synthesis, and Pharmacological Evaluation of Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl Sulfide 3 (BPTES) Analogs as Glutaminase Inhibitors

  摘要：

  Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) is a potent and selective allosteric inhibitor of kidney-type glutaminase (GLS) that has served as a molecular probe to determine the therapeutic potential of GLS inhibition. In an attempt to identify more potent GLS inhibitors with improved drug-like molecular properties, a series of BPTES analogs were synthesized and evaluated. Our structure activity relationship (SAR) studies revealed that some truncated analogs retained the potency of BPTES, presenting an opportunity to improve its aqueous solubility. One of the analogs, N-(5-{2-[2-(5-amino-[1,3,4]thiadiazol-2-yl)-ethylsulfanyl]-ethyl}-[1,3,4]thiadiazol-2-yl)-2-phenylacetamide 6, exhibited similar potency and better solubility relative to BPTES and attenuated the growth of P493 human lymphoma B cells in vitro as well as in a mouse xenograft model.

  DOI：

  10.1021/jm301191p

文献信息

• Glutaminase inhibitor discovery and nanoparticle-enhanced delivery for cancer therapy
  申请人：The Johns Hopkins University

  公开号：US10660861B2

  公开（公告）日：2020-05-26

  Currently available glutaminase inhibitors are generally poorly soluble, metabolically unstable, and/or require high doses, which together reduce their efficacy and therapeutic index. These can be formulated into nanoparticles and delivered safely and effectively for treatment of pancreatic cancer and other glutamine addicted cancers. Studies demonstrate that nanoparticle delivery of BPTES, relative to use of BPTES alone, can be safely administered and provides dramatically improved tumor drug exposure, resulting in greater efficacy. GLS inhibitors can be administered in higher concentrations with sub-100 nm nanoparticles, since the nanoparticles package the drug into “soluble” colloidal nanoparticles, and the nanoparticles deliver higher drug exposure selectively to the tumors due to the enhanced permeability and retention (EPR) effect. These factors result in sustained drug levels above the IC50 within the tumors for days, providing significantly enhanced efficacy compared to unencapsulated drug.

  目前可用的谷氨酰胺酶抑制剂通常溶解性差、代谢不稳定和/或需要高剂量，这些因素共同降低了其疗效和治疗指数。这些药物可配制成纳米颗粒，安全有效地用于治疗胰腺癌和其他谷氨酰胺上瘾的癌症。研究表明，与单独使用 BPTES 相比，纳米颗粒给药 BPTES 可以安全给药，并显著改善肿瘤药物暴露，从而提高疗效。使用 100 纳米以下的纳米颗粒可以施用更高浓度的 GLS 抑制剂，因为纳米颗粒将药物包装成 "可溶性 "胶体纳米颗粒，并且由于增强的渗透性和滞留（EPR）效应，纳米颗粒可以有选择性地向肿瘤提供更高的药物暴露量。这些因素使肿瘤内的药物浓度在数天内持续高于 IC50，与未封装的药物相比，疗效显著提高。
• GLUTAMINASE INHIBITOR DISCOVERY AND NANOPARTICLE-ENHANCED DELIVERY FOR CANCER THERAPY
  申请人：The Johns Hopkins University

  公开号：US20170209387A1

  公开（公告）日：2017-07-27

  Currently available glutaminase inhibitors are generally poorly soluble, metabolically unstable, and/or require high doses, which together reduce their efficacy and therapeutic index. These can be formulated into nanoparticles and delivered safely and effectively for treatment of pancreatic cancer and other glutamine addicted cancers. Studies demonstrate that nanoparticle delivery of BPTES, relative to use of BPTES alone, can be safely administered and provides dramatically improved tumor drug exposure, resulting in greater efficacy. GLS inhibitors can be administered in higher concentrations with sub-100 nm nanoparticles, since the nanoparticles package the drug into “soluble” colloidal nanoparticles, and the nanoparticles deliver higher drug exposure selectively to the tumors due to the enhanced permeability and retention (EPR) effect. These factors result in sustained drug levels above the IC50 within the tumors for days, providing significantly enhanced efficacy compared to unencapsulated drug.
• [EN] GLUTAMINASE INHIBITOR DISCOVERY AND NANOPARTICLE-ENHANCED DELIVERY FOR CANCER THERAPY<br/>[FR] DÉCOUVERTE D'INHIBITEURS DE LA GLUTAMINASE ET ADMINISTRATION AMÉLIORÉE PAR DES NANOPARTICULES POUR LA THÉRAPIE ANTICANCÉREUSE
  申请人：UNIV JOHNS HOPKINS

  公开号：WO2016007647A1

  公开（公告）日：2016-01-14

  Currently available glutaminase inhibitors are generally poorly soluble, metabolically unstable, and/or require high doses, which together reduce their efficacy and therapeutic index. These can be formulated into nanoparticles and delivered safely and effectively for treatment of pancreatic cancer and other glutamine addicted cancers. Studies demonstrate that nanoparticle delivery of BPTES, relative to use of BPTES alone, can be safely administered and provides dramatically improved tumor drug exposure, resulting in greater efficacy. GLS inhibitors can be administered in higher concentrations with sub- 100 nm nanoparticles, since the nanoparticles package the drug into "soluble" colloidal nanoparticles, and the nanoparticles deliver higher drug exposure selectively to the tumors due to the enhanced permeability and retention (EPR) effect. These factors result in sustained drug levels above the IC50 within the tumors for days, providing significantly enhanced efficacy compared to unencapsulated drug.
• Design, Synthesis, and Pharmacological Evaluation of Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl Sulfide 3 (BPTES) Analogs as Glutaminase Inhibitors
  作者：Krupa Shukla、Dana V. Ferraris、Ajit G. Thomas、Marigo Stathis、Bridget Duvall、Greg Delahanty、Jesse Alt、Rana Rais、Camilo Rojas、Ping Gao、Yan Xiang、Chi V. Dang、Barbara S. Slusher、Takashi Tsukamoto

  DOI：10.1021/jm301191p

  日期：2012.12.13

  Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) is a potent and selective allosteric inhibitor of kidney-type glutaminase (GLS) that has served as a molecular probe to determine the therapeutic potential of GLS inhibition. In an attempt to identify more potent GLS inhibitors with improved drug-like molecular properties, a series of BPTES analogs were synthesized and evaluated. Our structure activity relationship (SAR) studies revealed that some truncated analogs retained the potency of BPTES, presenting an opportunity to improve its aqueous solubility. One of the analogs, N-(5-2-[2-(5-amino-[1,3,4]thiadiazol-2-yl)-ethylsulfanyl]-ethyl}-[1,3,4]thiadiazol-2-yl)-2-phenylacetamide 6, exhibited similar potency and better solubility relative to BPTES and attenuated the growth of P493 human lymphoma B cells in vitro as well as in a mouse xenograft model.