7-methoxycinnoline-3-carboxylic acid | 929975-18-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 7-methoxycinnoline-3-carboxylic acid
• CAS: 929975-18-8
• 化学式: C₁₀H₈N₂O₃
• mdl: MFCD09383938
• 分子量: 204.185
• InChiKey: OQKNTWCKGQSTOC-UHFFFAOYSA-N

物化性质

• 沸点：
  414.9±53.0 °C(Predicted)
• 密度：
  1.393±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  72.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  7-methoxycinnoline-3-carboxylic acid 在 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 为溶剂， 生成 2-azidoethyl (5-acetamido-9-(7-methoxycinnoline-3-carboxamido)-3,5,9-trideoxy-D-glycero-α-D-galacto-2-nonulopyranosylonic acid)-(2→3)-β-D-galactopyranosyl-(1→4)-2-acetamido-2-deoxy-β-D-glucopyranoside
  参考文献：
  名称：

  In Silico-Aided Design of a Glycan Ligand of Sialoadhesin for in Vivo Targeting of Macrophages

  摘要：

  Cell-specific delivery of therapeutic agents using ligand targeting is gaining interest because of its potential for increased efficacy and reduced side effects. The challenge is to develop a suitable ligand for a cell-surface receptor that is selectively expressed on the desired cell. Sialoadhesin (Sn, Siglec-1, CD169), a sialic acid-binding immunoglobulin-like lectin (Siglec) expressed on subsets of resident and inflammatory macrophages, is an attractive target for the development of a ligand-targeted delivery system. Here we report the development of a high-affinity and selective ligancl for Sn that is an analogue of the natural ligand and is capable of targeting liposomal nanoparticles to Sn-expressing cells in vivo. An efficient in silico screen of a library of similar to 8400 carboxylic acids was the key to identifying novel 9-N-acyl-substituted N-acetylneuramic acid (Neu5Ac) substituents as potential lead compounds. A small panel of targets were selected from the screen and synthesized to evaluate their affinities and selectivities. The most potent of these Sn ligands, (4H-thieno[3,2-c]chromene-2-carbamoyl)-Neu5Ac alpha 2-3Gal beta 1-4GlcNAc ((TCC)Neu5Ac), was conjugated to lipids for display on a liposomal nanoparticle for evaluation of targeted delivery to cells. The (TCC)Neu5Ac liposomes were found to target liposomes selectively to cells expressing either murine or human Sn in vitro, and when administered to mice, they exhibited in vivo targeting to Sn-positive macrophages.

  DOI：

  10.1021/ja307501e

文献信息

• The exploration of aza-quinolines as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors with low brain exposure
  作者：Rodolfo Cadilla、David N. Deaton、Young Do、Patricia A. Elkins、Daniela Ennulat、Jeffrey H. Guss、Jason Holt、Michael R. Jeune、Andrew G. King、Jan C. Klapwijk、H. Fritz Kramer、Nicholas J. Kramer、Susan B. Laffan、Paresh I. Masuria、Alan V. McDougal、Paul N. Mortenson、Caterina Musetti、Gregory E. Peckham、Beth L. Pietrak、Chuck Poole、Daniel J. Price、Alan R. Rendina、Girish Sati、Gordon Saxty、Barry G. Shearer、Lisa M. Shewchuk、Helen F. Sneddon、Eugene L. Stewart、J. Darren Stuart、Dean N. Thomas、Stephen A. Thomson、Paris Ward、Joseph W. Wilson、Tiahshun Xu、Mark A. Youngman

  DOI：10.1016/j.bmc.2020.115791

  日期：2020.12

  GlaxoSmithKline and Astex Pharmaceuticals recently disclosed the discovery of the potent H-PGDS inhibitor GSK2894631A 1a (IC₅₀ = 9.9 nM) as part of a fragment-based drug discovery collaboration with Astex Pharmaceuticals. This molecule exhibited good murine pharmacokinetics, allowing it to be utilized to explore H-PGDS pharmacology in vivo. Yet, with prolonged dosing at higher concentrations, 1a induced CNS toxicity. Looking to attenuate brain penetration in this series, aza-quinolines, were prepared with the intent of increasing polar surface area. Nitrogen substitutions at the 6- and 8-positions of the quinoline were discovered to be tolerated by the enzyme. Subsequent structure activity studies in these aza-quinoline scaffolds led to the identification of 1,8-naphthyridine 1y (IC₅₀ = 9.4 nM) as a potent peripherally restricted H-PGDS inhibitor. Compound 1y is efficacious in four in vivo inflammatory models and exhibits no CNS toxicity.