3-(4-formyl-5-hydroxy-6-methyl-2-(naphthalen-1-ylmethyl)pyridin-3-yl)propanoic acid

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 3-(4-formyl-5-hydroxy-6-methyl-2-(naphthalen-1-ylmethyl)pyridin-3-yl)propanoic acid
• 英文别名: 3-[4-Formyl-5-hydroxy-6-methyl-2-(naphthalen-1-ylmethyl)pyridin-3-yl]propanoic acid；3-[4-formyl-5-hydroxy-6-methyl-2-(naphthalen-1-ylmethyl)pyridin-3-yl]propanoic acid
• 化学式: C₂₁H₁₉NO₄
• 分子量: 349.386
• InChiKey: AUWOHRUFVOQPRJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  87.5
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-萘乙酸 在 盐酸 、 manganese(IV) oxide 、 lithium aluminium tetrahydride 、 重铬酸吡啶 、 甲酸 、 四磷十氧化物 、 palladium 10% on activated carbon 、 水 、 氢气 、 sodium hydride 、 potassium carbonate 、 对甲苯磺酸 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 potassium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 乙醇 、 二氯甲烷 、 氯仿 、 丙酮 为溶剂， 反应 57.58h， 生成 3-(4-formyl-5-hydroxy-6-methyl-2-(naphthalen-1-ylmethyl)pyridin-3-yl)propanoic acid
  参考文献：
  名称：

  Design and synthesis of potent and selective P2X3 receptor antagonists derived from PPADS as potential pain modulators

  摘要：

  Pyridoxalphosphate-6-azopheny1-2',4'-disulfonate (7a, PPADS), a nonselective P2X receptor antagonist, was extensively modified to develop more stable, potent, and selective P2X(3) receptor antagonists as potential antinociceptive agents. Based on the results of our previous report, all strong anionic groups in PPADS including phosphate and sulfonate groups were changed to carboxylic acids or deleted. The unstable azo (-N=N-) linkage of 7a was transformed to more stable carbon-carbon, ether or amide linkages through the synthesis of the 5-hydroxyl-pyridine moieties with substituents at 2 position via a Diels-Alder reaction. This resulted in the retention of antagonistic activity (IC50 = 400 similar to 700 nM) at the hP2X(3) receptor in the two-electrode voltage clamp (TEVC) assay system on the Xenopus oocytes. Introduction of bulky aromatic groups at the carbon linker, as in compounds 13h-n, dramatically improved the selectivity profiles of hP2X(3) when compared with mP2X(1) and hP2X(7) receptors. Among the substituents tested at the 2-position, the m-phenoxybenzyl group showed optimum selectivity and potency at the hP2X(3) receptor. In searching for effective substituents at the 4- and 3-positions, we found that compound 36j, with 4-carboxaldehyde, 3-propenoic acid and 2-(m-phenoxy)benzyl groups, was the most potent and selective hP2X(3) receptor antagonist with an IC50 of 60 nM at hP2X(3) and marginal antagonistic activities of 10 mu M at mP2X(1) and hP2X(7). Furthermore, using an ex-vivo assay system, we found that compound 36j potently inhibited pain signaling in the rat dorsal horn with 20 mu M 36j displaying 65% inhibition while 20 mu M pregabalin, a clinically available drug, showed only 31% inhibition. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.10.026

文献信息

• Design and synthesis of potent and selective P2X3 receptor antagonists derived from PPADS as potential pain modulators
  作者：Joong-Heui Cho、Kwan-Young Jung、Younghwan Jung、Min Hye Kim、Hyojin Ko、Chul-Seung Park、Yong-Chul Kim

  DOI：10.1016/j.ejmech.2013.10.026

  日期：2013.12

  Pyridoxalphosphate-6-azopheny1-2',4'-disulfonate (7a, PPADS), a nonselective P2X receptor antagonist, was extensively modified to develop more stable, potent, and selective P2X(3) receptor antagonists as potential antinociceptive agents. Based on the results of our previous report, all strong anionic groups in PPADS including phosphate and sulfonate groups were changed to carboxylic acids or deleted. The unstable azo (-N=N-) linkage of 7a was transformed to more stable carbon-carbon, ether or amide linkages through the synthesis of the 5-hydroxyl-pyridine moieties with substituents at 2 position via a Diels-Alder reaction. This resulted in the retention of antagonistic activity (IC50 = 400 similar to 700 nM) at the hP2X(3) receptor in the two-electrode voltage clamp (TEVC) assay system on the Xenopus oocytes. Introduction of bulky aromatic groups at the carbon linker, as in compounds 13h-n, dramatically improved the selectivity profiles of hP2X(3) when compared with mP2X(1) and hP2X(7) receptors. Among the substituents tested at the 2-position, the m-phenoxybenzyl group showed optimum selectivity and potency at the hP2X(3) receptor. In searching for effective substituents at the 4- and 3-positions, we found that compound 36j, with 4-carboxaldehyde, 3-propenoic acid and 2-(m-phenoxy)benzyl groups, was the most potent and selective hP2X(3) receptor antagonist with an IC50 of 60 nM at hP2X(3) and marginal antagonistic activities of 10 mu M at mP2X(1) and hP2X(7). Furthermore, using an ex-vivo assay system, we found that compound 36j potently inhibited pain signaling in the rat dorsal horn with 20 mu M 36j displaying 65% inhibition while 20 mu M pregabalin, a clinically available drug, showed only 31% inhibition. (C) 2013 Elsevier Masson SAS. All rights reserved.