(S)-N-(4-(3-(1H-1,2,4-triazole-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazole-2-yl)-2-amino-3-methylbutanamide | 1188371-47-2

• 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: (S)-N-(4-(3-(1H-1,2,4-triazole-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazole-2-yl)-2-amino-3-methylbutanamide
• 英文别名: CKD-516 free base；(2S)-2-amino-3-methyl-N-[4-[3-(1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl]-1,3-thiazol-2-yl]butanamide
• CAS: 1188371-47-2
• 化学式: C₂₆H₂₈N₆O₅S
• 分子量: 536.612
• InChiKey: UKKRUIXIDCWALA-QFIPXVFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  38
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  172
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  (S)-N-(4-(3-(1H-1,2,4-triazole-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazole-2-yl)-2-amino-3-methylbutanamide 在 盐酸 作用下， 以 1,4-二氧六环 、 甲醇 、 水 为溶剂， 反应 0.33h， 以76%的产率得到(S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide hydrochloride
  参考文献：
  名称：

  Identification of CKD-516: A Potent Tubulin Polymerization Inhibitor with Marked Antitumor Activity against Murine and Human Solid Tumors

  摘要：

  Tubulin polymerization inhibitors had emerged as one of promising anticancer therapeutics because of their dual mechanism of action, i.e. apoptosis by cell-cycle arrest and VDA, vascular disrupting agent. VDAs are believed to be more efficient, less toxic, and several of them are currently undergoing clinical trials. To identify novel tubulin inhibitors that possess potent cytotoxicity and strong inhibition of tubulin polymerization as well as potent in vivo antitumor efficacy, we have utilized benzophenone scaffold. Complete SA R analysis of newly synthesized analogues that were prepared by incorporation of small heterocycles (C2, C4, and C5 position) into B-ring along with the evaluation of their in vitro cytotoxicity, tubulin polymerization inhibition, and in vivo antitumor activity allowed us to identify 22 (S516). Compound 22 was found to have potent cytotoxicity against several cancer cells including P-gp overexpressing MDR positive cell line (HCT15). It also induced cell cycle arrest at G(2)/M phase, which is associated with strong inhibition of tubulin polymerization. Its in vivo efficacy was improved by preparing its (L)-valine prodrug, 65 (CKD-516), which together with greatly improved aqueous solubility has shown marked antitumor efficacy against both murine tumors (CT26 and 3LL) and human xenogratfs (HCT116 and HCT15) in mice.

  DOI：

  10.1021/jm1002414
• 作为产物：
  描述：

  (S)-(9H-fluoren-9-ylmethyl) 1-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-ylamino)-3-methyl-1-oxobutan-2-ylcarbamate 在 哌啶 作用下， 以 乙腈 为溶剂， 反应 12.0h， 以71%的产率得到(S)-N-(4-(3-(1H-1,2,4-triazole-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazole-2-yl)-2-amino-3-methylbutanamide
  参考文献：
  名称：

  Identification of CKD-516: A Potent Tubulin Polymerization Inhibitor with Marked Antitumor Activity against Murine and Human Solid Tumors

  摘要：

  Tubulin polymerization inhibitors had emerged as one of promising anticancer therapeutics because of their dual mechanism of action, i.e. apoptosis by cell-cycle arrest and VDA, vascular disrupting agent. VDAs are believed to be more efficient, less toxic, and several of them are currently undergoing clinical trials. To identify novel tubulin inhibitors that possess potent cytotoxicity and strong inhibition of tubulin polymerization as well as potent in vivo antitumor efficacy, we have utilized benzophenone scaffold. Complete SA R analysis of newly synthesized analogues that were prepared by incorporation of small heterocycles (C2, C4, and C5 position) into B-ring along with the evaluation of their in vitro cytotoxicity, tubulin polymerization inhibition, and in vivo antitumor activity allowed us to identify 22 (S516). Compound 22 was found to have potent cytotoxicity against several cancer cells including P-gp overexpressing MDR positive cell line (HCT15). It also induced cell cycle arrest at G(2)/M phase, which is associated with strong inhibition of tubulin polymerization. Its in vivo efficacy was improved by preparing its (L)-valine prodrug, 65 (CKD-516), which together with greatly improved aqueous solubility has shown marked antitumor efficacy against both murine tumors (CT26 and 3LL) and human xenogratfs (HCT116 and HCT15) in mice.

  DOI：

  10.1021/jm1002414

文献信息

• Composition for preventing or treating cancer comprising a vascular disrupting agent and immune checkpoint inhibitor
  申请人：CHONG KUN DANG PHARMACEUTICAL CORP.

  公开号：US11045452B2

  公开（公告）日：2021-06-29

  The present disclosure provides a composition for preventing or treating cancer comprising (S)—N-(4-(3-(1H-1,2,4-triazole-1-yl)-4-(3,4,5-trimethoxy-benzoyl)phenyl)thiazole-2-yl)-2-amino-3-methylbutanamide or pharmaceutically acceptable salts thereof, and an immune checkpoint inhibitor. The composition of the present disclosure achieves an excellent cancer treatment effect.

  本公开提供了一种用于预防或治疗癌症的组合物，该组合物包含(S)-N-(4-(3-(1H-1,2,4-三唑-1-基)-4-(3,4,5-三甲氧基苯甲酰基)苯基)噻唑-2-基)-2-氨基-3-甲基丁酰胺或其药学上可接受的盐，以及一种免疫检查点抑制剂。本公开的组合物具有极佳的癌症治疗效果。
• Discovery of a potent tubulin polymerization inhibitor: Synthesis and evaluation of water-soluble prodrugs of benzophenone analog
  作者：Jaekwang Lee、Suyeal Bae、Seo-hee Lee、Hojin Choi、Young Hoon Kim、Soo Jin Kim、Gyu Tae Park、Seung Kee Moon、Dal-Hyun Kim、Sungsook Lee、Soon Kil Ahn、Nam Song Choi、Kyung Joo Lee

  DOI：10.1016/j.bmcl.2010.05.060

  日期：2010.11

  Prodrugs have proven to be very useful in enhancing aqueous solubility of sparingly water-soluble drugs, thereby increasing in vivo efficacy without a need of special excipients. In vitro and in vivo evaluations of a number of amino acid prodrugs of 1, a previously identified potent tubulin polymerization inhibitor and cytotoxic against various cancer cell lines led to the discovery of 3 center dot HCl (L-valine attached) which is highly efficacious in mouse xenografts bearing human cancer. Pharmacokinetic analysis in rats revealed that compound 1 was released immediately upon administration of 3 center dot HCl intravenously, with rapid clearance of 3 center dot HCl indicating the effective cleavage of prodrug. Compound 3 center dot HCl (CKD-516) has now been progressed to phase 1 clinical trial. (C) 2010 Published by Elsevier Ltd.
• J. Med. Chem. 2010, 53, 6337-6354
  作者：

  DOI：——

  日期：——
• BENZOPHENONE THIAZOLE DERIVATIVES USEFUL FOR INHIBITING FORMATION OF MICROTUBULE AND METHOD FOR PRODUCING THE SAME
  申请人：Chong Kun Dang Pharmaceutical Corp.

  公开号：EP2272845B1

  公开（公告）日：2015-03-04
• COMBINED COMPOSITION FOR PREVENTING OR TREATING CANCER COMPRISING A BENZOPHENONE THIAZOLE DERIVATIVE AS A VDA AND A TOPOISOMERASE INHIBITOR
  申请人：Chong Kun Dang Pharmaceutical Corp.

  公开号：EP3515443B1

  公开（公告）日：2022-06-22