5-chloro-6-(4-(phenylsulfonylcarbamoyl)piperazin-1-yl)nicotinic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 5-chloro-6-(4-(phenylsulfonylcarbamoyl)piperazin-1-yl)nicotinic acid
• 英文别名: 6-[4-(Benzenesulfonylcarbamoyl)piperazin-1-yl]-5-chloropyridine-3-carboxylic acid；6-[4-(benzenesulfonylcarbamoyl)piperazin-1-yl]-5-chloropyridine-3-carboxylic acid
• 化学式: C₁₇H₁₇ClN₄O₅S
• 分子量: 424.865
• InChiKey: NBNKMSXTXJETQO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  128
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  3-氨基-4-羟基吡啶盐酸盐 在 三乙胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 水 为溶剂， 反应 19.17h， 生成 5-chloro-6-(4-(phenylsulfonylcarbamoyl)piperazin-1-yl)nicotinic acid
  参考文献：
  名称：

  Synthesis, structure–property relationships and pharmacokinetic evaluation of ethyl 6-aminonicotinate sulfonylureas as antagonists of the P2Y12 receptor

  摘要：

  The present paper describes the development of a new series of P2Y(12) receptor antagonists based on our previously reported piperazinyl urea series 1 (IC50 binding affinity = 0.33 mu M, aq solubility <0.1 mu M, microsomal CLint (HLM) >= 300 mu M/min/mg). By replacement of the urea functionality with a sulfonylurea group we observed increased affinity along with improved stability and solubility as exemplified by 47 (IC50 binding affinity = 0.042 mu M, aq solubility = 90 mu M, microsomal CLint (HLM) = 70 mu M/min/mg). Further improvements in affinity and metabolic stability were achieved by replacing the central piperazine ring with a 3-aminoazetidine as exemplified by 3 (IC50 binding affinity = 0.0062 mu M, aq solubility = 83 mu M, microsomal CLint (HLM) = 28 mu M/min/mg). The improved affinity observed in the in vitro binding assay also translated to the potency observed in the WPA aggregation assay (47: 19 nM and 3: 9.5 nM) and the observed in vitro ADME properties translates to the in vivo PK properties observed in rat. In addition, we found that the chemical stability of the sulfonylureas during prolonged storage in solution was related to the sulfonyl urea linker and depended on the type of solvent and the substitution pattern of the sulfonyl urea functionality. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.04.007

文献信息

• Synthesis, structure–property relationships and pharmacokinetic evaluation of ethyl 6-aminonicotinate sulfonylureas as antagonists of the P2Y12 receptor
  作者：Peter Bach、Jonas Boström、Kay Brickmann、J.J.J. van Giezen、Robert D. Groneberg、Darren M. Harvey、Michael O'Sullivan、Fredrik Zetterberg

  DOI：10.1016/j.ejmech.2013.04.007

  日期：2013.7

  The present paper describes the development of a new series of P2Y(12) receptor antagonists based on our previously reported piperazinyl urea series 1 (IC50 binding affinity = 0.33 mu M, aq solubility <0.1 mu M, microsomal CLint (HLM) >= 300 mu M/min/mg). By replacement of the urea functionality with a sulfonylurea group we observed increased affinity along with improved stability and solubility as exemplified by 47 (IC50 binding affinity = 0.042 mu M, aq solubility = 90 mu M, microsomal CLint (HLM) = 70 mu M/min/mg). Further improvements in affinity and metabolic stability were achieved by replacing the central piperazine ring with a 3-aminoazetidine as exemplified by 3 (IC50 binding affinity = 0.0062 mu M, aq solubility = 83 mu M, microsomal CLint (HLM) = 28 mu M/min/mg). The improved affinity observed in the in vitro binding assay also translated to the potency observed in the WPA aggregation assay (47: 19 nM and 3: 9.5 nM) and the observed in vitro ADME properties translates to the in vivo PK properties observed in rat. In addition, we found that the chemical stability of the sulfonylureas during prolonged storage in solution was related to the sulfonyl urea linker and depended on the type of solvent and the substitution pattern of the sulfonyl urea functionality. (C) 2013 Elsevier Masson SAS. All rights reserved.