N-(3-((6-chlorothiazolo[5,4-b]pyridin-2-yl)methoxy)-2,6-difluorobenzoyl)-1-methylpiperidine-4-carboxamide | 1499168-63-6

• 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: N-(3-((6-chlorothiazolo[5,4-b]pyridin-2-yl)methoxy)-2,6-difluorobenzoyl)-1-methylpiperidine-4-carboxamide
• 英文别名: TXY541；N-[3-[(6-chloro-[1,3]thiazolo[5,4-b]pyridin-2-yl)methoxy]-2,6-difluorobenzoyl]-1-methylpiperidine-4-carboxamide
• CAS: 1499168-63-6
• 化学式: C₂₁H₁₉ClF₂N₄O₃S
• 分子量: 480.923
• InChiKey: WHLAOILNESDSJJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  113
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  3-[(6-氯噻唑并[5,4-b]吡啶-2-基)甲氧基]-2,6-二氟苯甲酰胺 、 N-甲基-4-哌啶甲酰氯盐酸盐 在 sodium hydride 、 sodium hydroxide 作用下， 以 mineral oil 为溶剂， 以300 mg的产率得到N-(3-((6-chlorothiazolo[5,4-b]pyridin-2-yl)methoxy)-2,6-difluorobenzoyl)-1-methylpiperidine-4-carboxamide
  参考文献：
  名称：

  Pharmacokinetics and in vivo antistaphylococcal efficacy of TXY541, a 1-methylpiperidine-4-carboxamide prodrug of PC190723

  摘要：

  The benzamide derivative PC190723 was among the first of a promising new class of FtsZ-directed antibacterial agents to be identified that exhibit potent antistaphylococcal activity. However, the compound is associated with poor drug-like properties. As part of an ongoing effort to develop FtsZ-targeting antibacterial agents with increased potential for clinical utility, we describe herein the pharmacodynamics, pharmacokinetics, in vivo antistaphylococcal efficacy, and mammalian cytotoxicity of TXY541, a novel 1-methylpiperidine-4-carboxamide prodrug of PC190723. TXY541 was found to be 143-times more soluble than PC190723 in an aqueous acidic vehicle (10 mM citrate, pH 2.6) suitable for both oral and intravenous in vivo administration. In staphylococcal growth media, TXY541 converts to PC190723 with a half-life of approximately 8 h. In 100% mouse serum, the TXY541-to-PC190723 conversion was much more rapid (with a half-life of approximately 3 mm), suggesting that the conversion of the prodrug in serum is predominantly enzyme-catalyzed. Pharmacokinetic analysis of both orally and intravenously administered TXY541 in mice yielded a half-life for the PC190723 conversion product of 0.56 h and an oral bioavailability of 29.6%. Whether administered orally or intravenously, TXY541 was found to be efficacious in vivo in mouse models of systemic infection with both methicillin-sensitive and methicillin-resistant S. aureus. Toxicological assessment of TXY541 against mammalian cells revealed minimal detectable cytotoxicity. The results presented here highlight TXY541 as a potential therapeutic agent that warrants further pre-clinical development. (C) 2013 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2013.10.010

文献信息

• [EN] ANTIMICROBIAL AGENTS<br/>[FR] AGENTS ANTIMICROBIENS
  申请人：UNIV RUTGERS

  公开号：WO2014074932A1

  公开（公告）日：2014-05-15

  The invention provides compounds of formula (I): wherein R1-R3, n, and W have any of the values defined in the specification, and salts thereof. The compounds have good solubility and are useful for treating bacterial infections.

  该发明提供了式（I）的化合物：其中R1-R3，n和W具有规范中定义的任何值，以及其盐。这些化合物具有良好的溶解性，并可用于治疗细菌感染。
• ANTIMICROBIAL AGENTS
  申请人：Rutgers, The State University of New Jersey

  公开号：US20150133465A1

  公开（公告）日：2015-05-14

  The invention provides compounds of formula (I): wherein R 1 -R 3 , n, and W have any of the values defined in the specification, and salts thereof. The compounds have good solubility and are useful for treating bacterial infections.

  该发明提供了式(I)的化合物： 其中R1-R3，n和W具有规范中定义的任何值，并且其盐。这些化合物具有良好的溶解性，可用于治疗细菌感染。
• Antimicrobial agents
  申请人：RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY

  公开号：US11129814B2

  公开（公告）日：2021-09-28

  The invention provides synthetic methods and synthetic intermediates that are useful for preparing the antibacterial compound:

  本发明提供了有助于制备抗菌化合物的合成方法和合成中间体：
• US9458150B2
  申请人：——

  公开号：US9458150B2

  公开（公告）日：2016-10-04
• Pharmacokinetics and in vivo antistaphylococcal efficacy of TXY541, a 1-methylpiperidine-4-carboxamide prodrug of PC190723
  作者：Malvika Kaul、Lilly Mark、Yongzheng Zhang、Ajit K. Parhi、Edmond J. LaVoie、Daniel S. Pilch

  DOI：10.1016/j.bcp.2013.10.010

  日期：2013.12

  The benzamide derivative PC190723 was among the first of a promising new class of FtsZ-directed antibacterial agents to be identified that exhibit potent antistaphylococcal activity. However, the compound is associated with poor drug-like properties. As part of an ongoing effort to develop FtsZ-targeting antibacterial agents with increased potential for clinical utility, we describe herein the pharmacodynamics, pharmacokinetics, in vivo antistaphylococcal efficacy, and mammalian cytotoxicity of TXY541, a novel 1-methylpiperidine-4-carboxamide prodrug of PC190723. TXY541 was found to be 143-times more soluble than PC190723 in an aqueous acidic vehicle (10 mM citrate, pH 2.6) suitable for both oral and intravenous in vivo administration. In staphylococcal growth media, TXY541 converts to PC190723 with a half-life of approximately 8 h. In 100% mouse serum, the TXY541-to-PC190723 conversion was much more rapid (with a half-life of approximately 3 mm), suggesting that the conversion of the prodrug in serum is predominantly enzyme-catalyzed. Pharmacokinetic analysis of both orally and intravenously administered TXY541 in mice yielded a half-life for the PC190723 conversion product of 0.56 h and an oral bioavailability of 29.6%. Whether administered orally or intravenously, TXY541 was found to be efficacious in vivo in mouse models of systemic infection with both methicillin-sensitive and methicillin-resistant S. aureus. Toxicological assessment of TXY541 against mammalian cells revealed minimal detectable cytotoxicity. The results presented here highlight TXY541 as a potential therapeutic agent that warrants further pre-clinical development. (C) 2013 Elsevier Inc. All rights reserved.