N-(1-((1-benzylpiperidin-4-yl)methyl)-3-(3-carbamimidoylphenyl)-2-oxohexahydropyrimidin-5-yl)-2-phenylacetamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: N-(1-((1-benzylpiperidin-4-yl)methyl)-3-(3-carbamimidoylphenyl)-2-oxohexahydropyrimidin-5-yl)-2-phenylacetamide
• 英文别名: N-[1-[(1-benzylpiperidin-4-yl)methyl]-3-(3-carbamimidoylphenyl)-2-oxo-1,3-diazinan-5-yl]-2-phenylacetamide
• 化学式: C₃₂H₃₈N₆O₂
• 分子量: 538.693
• InChiKey: BFOHAEDJCBXVHR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  40
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  106
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  异氰酸间氰基苯酯 在 4-二甲氨基吡啶 、 sodium tetrahydroborate 、 sodium azide 、 palladium 10% on activated carbon 、 盐酸羟胺 、 氢气 、 sodium hydride 、 臭氧 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， -78.0~85.0 ℃ 、344.75 kPa 条件下， 反应 29.83h， 生成 N-(1-((1-benzylpiperidin-4-yl)methyl)-3-(3-carbamimidoylphenyl)-2-oxohexahydropyrimidin-5-yl)-2-phenylacetamide
  参考文献：
  名称：

  Design and Synthesis of Nonpeptide Inhibitors of Hepatocyte Growth Factor Activation

  摘要：

  In this letter we report first nonpeptide inhibitors of hepatocyte growth factor (HGF) activation. These compounds inhibit the three proteases (matriptase, hepsin, and HGF activator) required for HGF maturation. We show that 6, 8a, 8b, and 8d block activation of fibroblast-derived pro-HGF, thus preventing fibroblast-induced scattering of DU145 prostate cancer cells. Compound 6 (SRI 31215) is very soluble (91 mu M) and has excellent microsome stability (human t(1/2) = 162 min; mouse t(1/2) = 296 min). In mouse 6 has an in vivo t(1/2) = 5.8 h following IV administration. The high solubility of 6 and IV tin make this compound a suitable prototype "triplex inhibitor" for the study of the inhibition of HGF activation in vivo.

  DOI：

  10.1021/acsmedchemlett.5b00357

文献信息

• [EN] INHIBITORS OF HEPATOCYTE GROWTH FACTOR [HGF] AND MACROPHAGE STIMULATING PROTEIN [MSP] MATURATION<br/>[FR] INHIBITEURS DE MATURATION DU FACTEUR DE CROISSANCE HÉPATOCYTAIRE (HGF] ET DE LA PROTÉINE DE STIMULATION DES MACROPHAGES [MSP]
  申请人：SOUTHERN RES INST

  公开号：WO2015184222A1

  公开（公告）日：2015-12-03

  Provided are certain cyclic urea compounds that are capable of inhibiting certain serine proteases, and especially the serine proteases matriptase, hepsin and hepatocyte growth factor activator (HGFA) involved in the maturation of hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP), and novel precursors thereof. Compounds of the present disclosure can be used to treat a number of disorders caused by or associated with abnormal matriptase, hepsin and HGFA protease activity by inhibiting the proteolytic cleavage of pro-HGF to mature HGF and pro-MSP to mature MSP caused by these enzymes. Compounds of the present disclosure can be used to treat disorders including precancerous conditions and cancer including metastatic disease, prevention and reversion of cancer resistance, and the inhibition of cancer stem cells. The compounds of this invention are applicable to the treatment of cancers of many tissue types including solid and liquid tumors.

  提供了一些能够抑制特定丝氨酸蛋白酶的环脲化合物，尤其是涉及肝细胞生长因子（HGF）和巨噬细胞刺激蛋白（MSP）成熟的丝氨酸蛋白酶matriptase、hepsin和肝细胞生长因子激活酶（HGFA），以及其新颖前体。本公开的化合物可用于治疗由或与异常matriptase、hepsin和HGFA蛋白酶活性相关的多种疾病，通过抑制这些酶引起的pro-HGF到成熟HGF和pro-MSP到成熟MSP的蛋白水解裂解。本公开的化合物可用于治疗包括癌前病变和癌症（包括转移性疾病、预防和逆转癌症耐药性以及抑制癌干细胞）在内的多种疾病。本发明的化合物适用于治疗多种组织类型的癌症，包括实体肿瘤和液体肿瘤。