ethyl (10S,13S,16S)-10,13-dibenzyl-16-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)-2,2-dimethyl-4,9,12,15-tetraoxo-3-oxa-5,8,11,14-tetraazanonadecan-19-oate | 1268279-57-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: ethyl (10S,13S,16S)-10,13-dibenzyl-16-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)-2,2-dimethyl-4,9,12,15-tetraoxo-3-oxa-5,8,11,14-tetraazanonadecan-19-oate
• CAS: 1268279-57-7
• 化学式: C₄₇H₅₈N₁₂O₈
• 分子量: 919.053
• InChiKey: OSLMOPAJSMBYAJ-KVBYWJEESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.76
• 重原子数：
  67.0
• 可旋转键数：
  21.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  287.87
• 氢给体数：
  7.0
• 氢受体数：
  15.0

反应信息

• 作为反应物：
  描述：

  ethyl (10S,13S,16S)-10,13-dibenzyl-16-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)-2,2-dimethyl-4,9,12,15-tetraoxo-3-oxa-5,8,11,14-tetraazanonadecan-19-oate 在 盐酸 、 水 作用下， 以 乙醇 为溶剂， 反应 1.0h， 以68.2%的产率得到MTX-(OEt)-α-Phe-Phe-NH-C2H4-NH2
  参考文献：
  名称：

  Synthesis and optimization of hyaluronic acid–methotrexate conjugates to maximize benefit in the treatment of osteoarthritis

  摘要：

  We previously reported that a conjugate of hyaluronic acid (HA) and methotrexate (MTX) could be a prototype for future osteoarthritis drugs having the efficacy of the two clinically validated agents but with a reduced risk of the systemic side effects of MTX by using HA as the drug delivery carrier. To identify a clinical candidate, we attempted optimization of a lead, conjugate 1. Initially, in fragmentation experiments with cathepsins, we optimized the peptide part of HA-MTX conjugates to be simpler and more susceptible to enzymatic cleavage. Then we optimized the peptide, the linker, the molecular weight, and the binding ratio of the MTX of the conjugates to inhibit proliferation of human fibroblast-like syno-viocytes in vitro and knee swelling in rat antigen-induced monoarthritis in vivo. Consequently, we found conjugate 30 (DK226) to be a candidate drug for the treatment of osteoarthritis. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.12.053
• 作为产物：
  描述：

  H-Glu(OEt)PhePhe-NH-C2H4-NH-Boc 、 4-[N-(2,4-二氨基-6-蝶啶甲基)-N-甲氨基]苯甲酸半盐酸盐n水 在 N-甲基吗啉 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N-甲基吡咯烷酮 为溶剂， 反应 4.0h， 以92.4%的产率得到ethyl (10S,13S,16S)-10,13-dibenzyl-16-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)-2,2-dimethyl-4,9,12,15-tetraoxo-3-oxa-5,8,11,14-tetraazanonadecan-19-oate
  参考文献：
  名称：

  Synthesis and optimization of hyaluronic acid–methotrexate conjugates to maximize benefit in the treatment of osteoarthritis

  摘要：

  We previously reported that a conjugate of hyaluronic acid (HA) and methotrexate (MTX) could be a prototype for future osteoarthritis drugs having the efficacy of the two clinically validated agents but with a reduced risk of the systemic side effects of MTX by using HA as the drug delivery carrier. To identify a clinical candidate, we attempted optimization of a lead, conjugate 1. Initially, in fragmentation experiments with cathepsins, we optimized the peptide part of HA-MTX conjugates to be simpler and more susceptible to enzymatic cleavage. Then we optimized the peptide, the linker, the molecular weight, and the binding ratio of the MTX of the conjugates to inhibit proliferation of human fibroblast-like syno-viocytes in vitro and knee swelling in rat antigen-induced monoarthritis in vivo. Consequently, we found conjugate 30 (DK226) to be a candidate drug for the treatment of osteoarthritis. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.12.053