(S)-5-Biphenyl-4-yl-4-(3-carboxy-propionylamino)-pentanoic acid

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (S)-5-Biphenyl-4-yl-4-(3-carboxy-propionylamino)-pentanoic acid
• 英文别名: (4S)-4-(3-carboxypropanoylamino)-5-(4-phenylphenyl)pentanoic acid
• 化学式: C₂₁H₂₃NO₅
• 分子量: 369.417
• InChiKey: VRSUMLWKSZXAQR-SFHVURJKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  27
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  104
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  Sodium; 3-((S)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-propylcarbamoyl)-propionate 在 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 生成 (S)-5-Biphenyl-4-yl-4-(3-carboxy-propionylamino)-pentanoic acid
  参考文献：
  名称：

  Dicarboxylic Acid Dipeptide Neutral Endopeptidase Inhibitors

  摘要：

  The synthesis of three series of dicarboxylic acid dipeptide neutral endopeptidase 24.11 (NEP) inhibitors is described. In particular, the amino butyramide 21a exhibited potent NEP inhibitory activity (IC50 = 5.0 nM) in vitro and in vivo. Blood levels of 21a were determined using an ex vivo method by measuring plasma inhibitory activity in conscious rats, mongrel dogs, and cynomolgus monkeys. Free drug concentrations were 10-1500 times greater than the inhibitory constant for NEP over the course of a 6 h experiment. A good correlation of free drug concentrations was obtained when comparing values determined by the ex vivo analysis to those calculated from direct HPLC measurements. Plasma atrial natriuretic factor (exogenous) levels were elevated in rats and dogs after oral administration of 19a. Urinary volume and urinary sodium excretion were also potentiated in anesthetized dogs treated with 21a.

  DOI：

  10.1021/jm00010a014

文献信息

• Biaryl substituted 4-amino-butyric acid amides
  申请人：CIBA-GEIGY AG

  公开号：EP0555175A1

  公开（公告）日：1993-08-11

  The invention relates to biaryl substituted 4-amino-butyric acid derivatives of formula I wherein COX and COX' independently represent carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester or amide; R1 represents hydrogen, lower alkyl, C3-C7-cycloalkyl-lower alkyl, aryl-lower alkyl, biaryl-lower alkyl, lower alkoxy, aryl-lower alkoxy, aryloxy, N-lower alkylamino, N,N-di-lower alkylamino, N-aryl-lower alkylamino, N,N-di-aryl-lower alkylamino, N-arylamino, N,N-diarylamino, lower alkanoylamino, aryl-lower alkanoylamino or aroylamino; R2 represents hydrogen, hydroxy, lower alkoxy, lower alkyl, aryl-lower alkyl, C3-C7-cycloalkyl-lower alkyl, amino-lower alkyl, hydroxy-lower alkyl, lower alkylthio-lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkylthio-lower alkyl or aryl-lower alkoxy-lower alkyl ; biaryl represents phenyl substituted by carbocyclic or heterocyclic aryl ; A represents a direct bond, lower alkylene, phenylene or cyclohexylene ; m represents 1 or zero, provided that m represents 1 when A is a direct bond ; or pharmaceutically acceptable salts thereof ; pharmaceutical compositions comprising said compounds ; methods for the preparation of said compounds and for the preparation of intermediates; and methods of treating disorders in mammals which are responsive to the inhibition of neutral endopeptidases by administration of said compounds to mammals in need of such treatment.

  本发明涉及式 I 的双芳基取代的 4-氨基丁酸衍生物 其中 COX 和 COX'独立地代表羧基或以药学上可接受的酯或酰胺形式衍生的羧基；R1 代表氢、低级烷基、C3-C7-环烷基-低级烷基、芳基-低级烷基、双芳基-低级烷基、低级烷氧基、芳基-低级烷氧基、芳氧基、N-低级烷基氨基、N,N-二低级烷基氨基、N-芳基-低级烷基氨基、N,N-二芳基-低级烷基氨基、N-芳基氨基、N,N-二芳基氨基、低级烷酰氨基、芳基-低级烷酰氨基或芳基氨基；R2 代表氢、羟基、低级烷氧基、低级烷基、芳基-低级烷基、C3-C7-环烷基-低级烷基、氨基-低级烷基、羟基-低级烷基、低级烷硫基-低级烷基、低级烷氧基-低级烷基、芳基-低级烷硫基-低级烷基或芳基-低级烷氧基-低级烷基；双芳基代表被碳环或杂环芳基取代的苯基；A 代表直接键、低级亚烷基、亚苯基或环己基；m 代表 1 或 0，但当 A 为直接键时，m 代表 1；或其药学上可接受的盐；包含所述化合物的药物组合物；制备所述化合物和制备中间体的方法；以及通过向需要治疗的哺乳动物施用所述化合物来治疗对中性内肽酶的抑制有反应的哺乳动物疾病的方法。
• Dicarboxylic Acid Dipeptide Neutral Endopeptidase Inhibitors
  作者：Gary M. Ksander、Raj D. Ghai、Reynalda deJesus、Clive Diefenbacher、Andrew Yuan、Carol Berry、Yumi Sakane、Angelo Trapani

  DOI：10.1021/jm00010a014

  日期：1995.5

  The synthesis of three series of dicarboxylic acid dipeptide neutral endopeptidase 24.11 (NEP) inhibitors is described. In particular, the amino butyramide 21a exhibited potent NEP inhibitory activity (IC50 = 5.0 nM) in vitro and in vivo. Blood levels of 21a were determined using an ex vivo method by measuring plasma inhibitory activity in conscious rats, mongrel dogs, and cynomolgus monkeys. Free drug concentrations were 10-1500 times greater than the inhibitory constant for NEP over the course of a 6 h experiment. A good correlation of free drug concentrations was obtained when comparing values determined by the ex vivo analysis to those calculated from direct HPLC measurements. Plasma atrial natriuretic factor (exogenous) levels were elevated in rats and dogs after oral administration of 19a. Urinary volume and urinary sodium excretion were also potentiated in anesthetized dogs treated with 21a.