4-methyl-1-(S)-({5-[(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-carbamoyl]pyrazolo[1,5-a]pyrimidine-7-carbonyl}amino)indan-5-carboxylic acid tert-butyl ester | 1354013-32-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• 英文名称: 4-methyl-1-(S)-({5-[(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-carbamoyl]pyrazolo[1,5-a]pyrimidine-7-carbonyl}amino)indan-5-carboxylic acid tert-butyl ester
• 英文别名: tert-butyl (1S)-4-methyl-1-[[5-[(3-oxo-4H-1,4-benzoxazin-6-yl)methylcarbamoyl]pyrazolo[1,5-a]pyrimidine-7-carbonyl]amino]-2,3-dihydro-1H-indene-5-carboxylate
• CAS: 1354013-32-3
• 化学式: C₃₂H₃₂N₆O₆
• 分子量: 596.643
• InChiKey: GMIUPSIEJZJAKM-QFIPXVFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  44
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  153
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  4-methyl-1-(S)-({5-[(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-carbamoyl]pyrazolo[1,5-a]pyrimidine-7-carbonyl}amino)indan-5-carboxylic acid tert-butyl ester 在 甲酸 作用下， 反应 2.0h， 以95%的产率得到4-methyl-1-(S)-({5-[(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)carbamoyl]pyrazolo[1,5-a]pyrimidine-7-carbonyl}amino)indan-5-carboxylic acid
  参考文献：
  名称：

  Discovery and Evaluation of a Non-Zn Chelating, Selective Matrix Metalloproteinase 13 (MMP-13) Inhibitor for Potential Intra-articular Treatment of Osteoarthritis

  摘要：

  Osteoarthritis (OA) is a nonsystemic disease for which no oral or parenteral disease-modifying osteoarthritic drug (DMOAD) is currently available. Matrix metalloproteinase 13 (MMP-13) has attracted attention as a target with disease-modifying potential because of its major role in tissue destruction associated with OA. Being localized to one or a few joints, OA is amenable to intra-articular (IA) therapy, which has distinct advantages over oral therapies in terms of increasing therapeutic index, by maximizing drug delivery to cartilage and minimizing systemic exposure. Here we report on the synthesis and biological evaluation of a non-zinc binding MMP-13 selective inhibitor, 4-methyl-1-(S)-({5-[(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)carbamoyl]pyrazolo[1,5-a]pyrimidine-7-carbonyl}amino)indan-5-carboxylic acid (1), that is uniquely suited as a potential IA-DMOAD: it has long durability in the joint, penetrates cartilage effectively, exhibits nearly no detectable systemic exposure, and has remarkable efficacy.

  DOI：

  10.1021/jm201152u
• 作为产物：
  描述：

  乙酰丙酮酸甲酯 在 N-甲基吗啉 、 叔丁基过氧化氢 、 selenium(IV) oxide 、 potassium peroxymonosulfate 、 N-羟基-7-氮杂苯并三氮唑 、 水 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 lithium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 癸烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 95.0h， 生成 4-methyl-1-(S)-({5-[(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-carbamoyl]pyrazolo[1,5-a]pyrimidine-7-carbonyl}amino)indan-5-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Discovery and Evaluation of a Non-Zn Chelating, Selective Matrix Metalloproteinase 13 (MMP-13) Inhibitor for Potential Intra-articular Treatment of Osteoarthritis

  摘要：

  Osteoarthritis (OA) is a nonsystemic disease for which no oral or parenteral disease-modifying osteoarthritic drug (DMOAD) is currently available. Matrix metalloproteinase 13 (MMP-13) has attracted attention as a target with disease-modifying potential because of its major role in tissue destruction associated with OA. Being localized to one or a few joints, OA is amenable to intra-articular (IA) therapy, which has distinct advantages over oral therapies in terms of increasing therapeutic index, by maximizing drug delivery to cartilage and minimizing systemic exposure. Here we report on the synthesis and biological evaluation of a non-zinc binding MMP-13 selective inhibitor, 4-methyl-1-(S)-({5-[(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)carbamoyl]pyrazolo[1,5-a]pyrimidine-7-carbonyl}amino)indan-5-carboxylic acid (1), that is uniquely suited as a potential IA-DMOAD: it has long durability in the joint, penetrates cartilage effectively, exhibits nearly no detectable systemic exposure, and has remarkable efficacy.

  DOI：

  10.1021/jm201152u

文献信息

• Discovery and Evaluation of a Non-Zn Chelating, Selective Matrix Metalloproteinase 13 (MMP-13) Inhibitor for Potential Intra-articular Treatment of Osteoarthritis
  作者：Christian Gege、Bagna Bao、Harald Bluhm、Jürgen Boer、Brian M. Gallagher、Brian Korniski、Timothy S. Powers、Christoph Steeneck、Arthur G. Taveras、Vijaykumar M. Baragi

  DOI：10.1021/jm201152u

  日期：2012.1.26

  Osteoarthritis (OA) is a nonsystemic disease for which no oral or parenteral disease-modifying osteoarthritic drug (DMOAD) is currently available. Matrix metalloproteinase 13 (MMP-13) has attracted attention as a target with disease-modifying potential because of its major role in tissue destruction associated with OA. Being localized to one or a few joints, OA is amenable to intra-articular (IA) therapy, which has distinct advantages over oral therapies in terms of increasing therapeutic index, by maximizing drug delivery to cartilage and minimizing systemic exposure. Here we report on the synthesis and biological evaluation of a non-zinc binding MMP-13 selective inhibitor, 4-methyl-1-(S)-(5-[(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)carbamoyl]pyrazolo[1,5-a]pyrimidine-7-carbonyl}amino)indan-5-carboxylic acid (1), that is uniquely suited as a potential IA-DMOAD: it has long durability in the joint, penetrates cartilage effectively, exhibits nearly no detectable systemic exposure, and has remarkable efficacy.