4-((4-(1-methyl-1H-indazol-7-yl)-1,4-diazepan-1-yl)methyl)-2-phenylthiazole | 1226687-59-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡唑类
• 英文名称: 4-((4-(1-methyl-1H-indazol-7-yl)-1,4-diazepan-1-yl)methyl)-2-phenylthiazole
• 英文别名: 4-[[4-(1-Methylindazol-7-yl)-1,4-diazepan-1-yl]methyl]-2-phenyl-1,3-thiazole；4-[[4-(1-methylindazol-7-yl)-1,4-diazepan-1-yl]methyl]-2-phenyl-1,3-thiazole
• CAS: 1226687-59-7
• 化学式: C₂₃H₂₅N₅S
• 分子量: 403.551
• InChiKey: KZOZGINZZQXYTM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  65.4
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  1,4-二氮杂环庚烷-1-甲酸叔丁酯 在 tris-(dibenzylideneacetone)dipalladium(0) 、 三乙酰氧基硼氢化钠 、 sodium t-butanolate 、 2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 1,2-二氯乙烷 为溶剂， 反应 22.5h， 生成 4-((4-(1-methyl-1H-indazol-7-yl)-1,4-diazepan-1-yl)methyl)-2-phenylthiazole
  参考文献：
  名称：

  Discovery of a Novel Small-Molecule Modulator of C–X–C Chemokine Receptor Type 7 as a Treatment for Cardiac Fibrosis

  摘要：

  C-X-C chemokine receptor type 7 (CXCR7) is involved in cardiac and immune pathophysiology. We report the discovery of a novel 1,4-diazepine CXCR7 modulator, demonstrating for the first time the role of pharmacological CXCR7 intervention in cardiac repair. Structure activityrelationship (SAR) studies demonstrated that a net reduction in lipophilicity (log D) and an incorporation of saturated ring systems yielded compounds with good CXCR7 potencies and improvements in oxidative metabolic stability in human-liver microsomes (HLM). Tethering an ethylene amide further improved the selectivity profile (e.g., for compound 18, CXCR7 K-i = 13 nM, adrenergic alpha la K-b > 10 000 nM, and adrenergic beta 2 K-b > 10 000 nM). The subcutaneous administration of 18 in mice led to a statistically significant increase in circulating concentrations of plasma stromal-cell-derived factor la (SDF-1 alpha) of approximately 2-fold. Chronic dosing of compound 18 in a mouse model of isoproterenol-induced cardiac injury further resulted in a statistically significant reduction of cardiac fibrosis.

  DOI：

  10.1021/acs.jmedchem.8b00190

文献信息

• MODULATORS OF CXCR7
  申请人：Chen Xi

  公开号：US20100150831A1

  公开（公告）日：2010-06-17

  Compounds having formula I, or pharmaceutically acceptable salts, hydrates or N-oxides thereof are provided and are useful for binding to CXCR7, and treating diseases that are dependent, at least in part, on CXCR7 activity. Accordingly, the present invention provides in further aspects, compositions containing one or more of the above-noted compounds in admixture with a pharmaceutically acceptable excipient.

  本发明提供公式I的化合物，或其药学上可接受的盐、水合物或N-氧化物，用于结合CXCR7并治疗至少在一定程度上依赖于CXCR7活性的疾病。因此，本发明在进一步方面提供含有上述化合物之一或多个的组合物，与药学上可接受的载体混合使用。
• US8288373B2
  申请人：——

  公开号：US8288373B2

  公开（公告）日：2012-10-16
• Discovery of a Novel Small-Molecule Modulator of C–X–C Chemokine Receptor Type 7 as a Treatment for Cardiac Fibrosis
  作者：Elnaz Menhaji-Klotz、Kevin D. Hesp、Allyn T. Londregan、Amit S. Kalgutkar、David W. Piotrowski、Markus Boehm、Kun Song、Tim Ryder、Kevin Beaumont、Rhys M. Jones、Karen Atkinson、Janice A. Brown、John Litchfield、Jun Xiao、Daniel P. Canterbury、Kristen Burford、Benjamin A. Thuma、Chris Limberakis、Wenhua Jiao、Scott W. Bagley、Saket Agarwal、Danielle Crowell、Stephen Pazdziorko、Jessica Ward、David A. Price、Valerie Clerin

  DOI：10.1021/acs.jmedchem.8b00190

  日期：2018.4.26

  C-X-C chemokine receptor type 7 (CXCR7) is involved in cardiac and immune pathophysiology. We report the discovery of a novel 1,4-diazepine CXCR7 modulator, demonstrating for the first time the role of pharmacological CXCR7 intervention in cardiac repair. Structure activityrelationship (SAR) studies demonstrated that a net reduction in lipophilicity (log D) and an incorporation of saturated ring systems yielded compounds with good CXCR7 potencies and improvements in oxidative metabolic stability in human-liver microsomes (HLM). Tethering an ethylene amide further improved the selectivity profile (e.g., for compound 18, CXCR7 K-i = 13 nM, adrenergic alpha la K-b > 10 000 nM, and adrenergic beta 2 K-b > 10 000 nM). The subcutaneous administration of 18 in mice led to a statistically significant increase in circulating concentrations of plasma stromal-cell-derived factor la (SDF-1 alpha) of approximately 2-fold. Chronic dosing of compound 18 in a mouse model of isoproterenol-induced cardiac injury further resulted in a statistically significant reduction of cardiac fibrosis.