[(2R)-1-[(2S)-2-氨基-3-甲基丁酰基]吡咯烷-2-基]硼酸 | 149682-77-9

• 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
• 中文名称: [(2R)-1-[(2S)-2-氨基-3-甲基丁酰基]吡咯烷-2-基]硼酸
• 中文别名: Talabostat;[(2R)-1-[(2S)-2-氨基-3-甲基丁酰基]吡咯烷-2-基]硼酸
• 英文名称: talabostat
• 英文别名: Val-boroPro；PT-100；VbP；[(2R)-1-[(2S)-2-amino-3-methylbutanoyl]pyrrolidin-2-yl]boronic acid
• CAS: 149682-77-9
• 化学式: C₉H₁₉BN₂O₃
• 分子量: 214.072
• InChiKey: FKCMADOPPWWGNZ-YUMQZZPRSA-N

物化性质

• 沸点：
  421.4±55.0 °C(Predicted)
• 密度：
  1.15
• 溶解度：
  二甲基亚砜：≥40 mg/ml（186.85mM）

计算性质

• 辛醇/水分配系数(LogP)：
  -1.03
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  86.8
• 氢给体数：
  3
• 氢受体数：
  4

安全信息

• 海关编码：
  2933990090

制备方法与用途

生物活性

Talabostat（Val-boroPro；PT100）是一种口服、非选择性的二肽基肽酶 IV (DPP-IV) 抑制剂，IC50 < 4 nM，Ki = 0.18 nM，并且是第一个临床成纤维细胞活化蛋白 (FAP) 抑制剂（IC50 = 560 nM），同时抑制 DPP8/9 （IC50 = 4/11 nM，Ki = 1.5/0.76 nM）以及静息细胞脯氨酸二肽酶 (QPP)（IC50 = 310 nM）、DPP2 和一些其他 DASH 家族酶。它具有抗肿瘤和造血刺激活性。

靶点

• IC50: <4 nM (DPP-IV)，4/11 nM (DPP8/9)，310 nM (QPP)，560 nM (FAP)
• Ki: 0.18 nM (DPP-IV)，1.5/0.76 nM (DPP8/9)

体外研究

通过水解 N-末端 Xaa-Pro 或 Xaa-Ala 残基，Talabostat（Val-boroPro）抑制二肽酶如 FAP，从而促进细胞因子和趋化因子的产生以及特异性 T 细胞免疫和 T 细胞依赖性活性。Talabostat（Val-boroPro）竞争性地抑制 DPP 活性的 FAP 和 CD26/DPP-IV，并与催化位点有高度亲和力。

体内研究

在 WEHI 164 成纤维肉瘤、EL4 和 A20/2J 脾淋巴瘤模型中，Talabostat（Val-boroPro）能够促使肿瘤的消退和排斥。抗肿瘤效应似乎涉及肿瘤特异性 CTL 及保护性免疫记忆。对 WEHI 164 注射的小鼠进行 Talabostat（Val-boroPro）治疗后，观察到与 T 细胞激活和趋化相关的细胞因子 mRNA 表达增加。

反应信息

• 作为产物：
  描述：

  生成 [(2R)-1-[(2S)-2-氨基-3-甲基丁酰基]吡咯烷-2-基]硼酸
  参考文献：
  名称：

  J. Med. Chem. 2013. 56, 3467-3477

  摘要：

  DOI：

文献信息

• Identification of Selective and Potent Inhibitors of Fibroblast Activation Protein and Prolyl Oligopeptidase
  作者：Sarah E. Poplawski、Jack H. Lai、Youhua Li、Zhiping Jin、Yuxin Liu、Wengen Wu、Yong Wu、Yuhong Zhou、James L. Sudmeier、David G. Sanford、William W. Bachovchin

  DOI：10.1021/jm400351a

  日期：2013.5.9

  Fibroblast activation protein (FAP) is a serine protease selectively expressed on reactive stromal fibroblasts of epithelial carcinomas. It is widely believed to play a role in tumor invasion and metastasis and therefore to represent a potential new drug target for cancer. Investigation into its biological function, however, has been hampered by the current unavailability of selective inhibitors. The challenge has been in identifying inhibitors that are selective for PAP over both the dipeptidyl peptidases (DPPs), with which it shares exopeptidase specificity, and prolyl oligopeptidase (PREP), with which it shares endopeptidase specificity. Here, we report the first potent FAP inhibitor with selectivity over both the DPPs and PREP, N-(pyridine-4-carbonyl)-D-Ala-boroPro (ARI-3099, 6). We also report a similarly potent and selective PREP inhibitor, N-(pyridine-3-carbonyl)-Val-boroPro (ARI-3531, 22). Both are boronic acid based inhibitors, demonstrating that high selectivity can be achieved using this electrophile. The inhibitors are stable, easy to synthesize, and should prove to be useful in helping to elucidate the biological functions of these two unique and interesting enzymes, as well as their potential as drug targets.
• Pro-Soft Val-boroPro: A Strategy for Enhancing in Vivo Performance of Boronic Acid Inhibitors of Serine Proteases
  作者：Sarah E. Poplawski、Jack H. Lai、David G. Sanford、James L. Sudmeier, Wengen Wu、William W. Bachovchin

  DOI：10.1021/jm100972f

  日期：2011.4.14

  Val-boroPro, 1, is a potent, but relatively nonspecific inhibitor of the prolyl peptidases. It has antihyperglycemic activity from inhibition of DPPIV but also striking anticancer activity and a toxicity for which the mechanisms are unknown. 1 cyclizes at physiological pH, which attenuates its inhibitory potency > 100-fold, which is a "soft drug" effect. Here we show that this phenomenon can be exploited to create prodrugs with unique properties and potential for selective in vivo targeting. Enzyme-mediated release delivers 1 to the target in the active form at physiological pH; cyclization attenuates systemic pharmacological effects from subsequent diffusion. This "pro-soft" design is demonstrated with a construct activated by and targeted to DPPIV, including in vivo results showing improved antihyperglycemic activity and reduced toxicity relative to I. Pro-soft derivatives of 1 can help to illuminate the mechanisms underlying the three biological activities, or to help localize 1 at a tumor and thereby lead to improved anticancer agents with reduced toxicity. The design concept can also be applied to a variety of other boronic acid inhibitors.
• Org. Process Res. Dev. 2002, 6, 814-816
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• CN114957305
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