A-78030 | 142707-90-2

• 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: A-78030
• 英文别名: (2S,4S,5S)-N-(3-aminopropyl)-6-cyclohexyl-4-hydroxy-5-[[(2S)-2-[(2S)-1-[4-(methoxymethoxy)piperidin-1-yl]-1-oxo-3-phenylpropan-2-yl]oxyhexanoyl]amino]-2-propan-2-ylhexanamide
• CAS: 142707-90-2
• 化学式: C₄₀H₆₈N₄O₇
• 分子量: 717.003
• InChiKey: XLRKCJWLCJXIIN-LTLCPEALSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  51
• 可旋转键数：
  23
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  152
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  A-78030 以 乙醇 、 水 、 乙腈 为溶剂， 反应 96.0h， 生成 N-[3-(N-cyano-N'-methylguanidino)propyl]-(2S,4S,5S,1'S,2'S)-5-[2-(1-{[4-(methoxymethoxy)piperidin-1-yl]carbonyl}-2-phenylethoxy)hexanamido]-6-cyclohexyl-4-hydroxy-2-isopropylhexanamide
  参考文献：
  名称：

  Nonpeptide Renin Inhibitors with Good Intraduodenal Bioavailability and Efficacy in Dog

  摘要：

  The aim of this study was the discovery of nonpeptide renin inhibitors with much improved oral absorption, bioavailability, and efficacy, for use as antihypertensive agents. Our prior efforts led to the identification of A-74273 [1, R = 3-(4-morpholino)propyl], with a bioavailability of 26 +/- 10% [10 mg/kg intraduodenally (id), dog]. In vivo metabolism studies of A-74273 showed that the morpholino moiety underwent metabolic degradation. Computer modeling of A-74273 bound to renin indicated that the C-terminus was involved in a hydrogen-bonding network. New C-terminal groups were examined in two series of nonpeptides for effects on renin binding potency, lipophilicity (log P), and aqueous solubility. Those groups which possessed multiple hydrogen-bonding ability (3,5-diaminotriazole, cyanoguanidines, morpholino) provided particularly potent renin binding. Intraduodenal bioavailabilities of selected compounds, evaluated in rats, ferrets, and dogs, were higher for inhibitors with moderate solubility as well as moderate lipophilicity, in general. Although the absolute values varied substantially among species, the relative ordering of the inhibitors in terms of absorption and bioavailablity was reasonably consistent. Such well absorbed inhibitors (e.g. 41, 44, and 51) were demonstrated as highly efficacious hypotensive agents in the salt-depleted dog. We report here the discovery of a series of efficacious nonpeptide renin inhibitors based on the 3-azaglutaramide P-2-P-4 replacement, the best of which showed id bioavailabilities > 50% in dog.

  DOI：

  10.1021/jm00045a003
• 作为产物：
  描述：

  2-(S)-((3-(tert-butyloxycarbonyl)-2,2-dimethyl-4(S)-(cyclohexylmethyl)-5(S)-oxazolidinyl)methyl)-3-methylbutanoic acid 在 palladium on activated charcoal N-甲基吗啉 、 水 、 氢气 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， -23.0~25.0 ℃ 、101.33 kPa 条件下， 反应 136.0h， 生成 A-78030
  参考文献：
  名称：

  Nonpeptide Renin Inhibitors with Good Intraduodenal Bioavailability and Efficacy in Dog

  摘要：

  The aim of this study was the discovery of nonpeptide renin inhibitors with much improved oral absorption, bioavailability, and efficacy, for use as antihypertensive agents. Our prior efforts led to the identification of A-74273 [1, R = 3-(4-morpholino)propyl], with a bioavailability of 26 +/- 10% [10 mg/kg intraduodenally (id), dog]. In vivo metabolism studies of A-74273 showed that the morpholino moiety underwent metabolic degradation. Computer modeling of A-74273 bound to renin indicated that the C-terminus was involved in a hydrogen-bonding network. New C-terminal groups were examined in two series of nonpeptides for effects on renin binding potency, lipophilicity (log P), and aqueous solubility. Those groups which possessed multiple hydrogen-bonding ability (3,5-diaminotriazole, cyanoguanidines, morpholino) provided particularly potent renin binding. Intraduodenal bioavailabilities of selected compounds, evaluated in rats, ferrets, and dogs, were higher for inhibitors with moderate solubility as well as moderate lipophilicity, in general. Although the absolute values varied substantially among species, the relative ordering of the inhibitors in terms of absorption and bioavailablity was reasonably consistent. Such well absorbed inhibitors (e.g. 41, 44, and 51) were demonstrated as highly efficacious hypotensive agents in the salt-depleted dog. We report here the discovery of a series of efficacious nonpeptide renin inhibitors based on the 3-azaglutaramide P-2-P-4 replacement, the best of which showed id bioavailabilities > 50% in dog.

  DOI：

  10.1021/jm00045a003

文献信息

• Nonpeptide Renin Inhibitors with Good Intraduodenal Bioavailability and Efficacy in Dog
  作者：Steven A. Boyd、Anthony K. L. Fung、William R. Baker、Robert A. Mantei、Herman H. Stein、Jerome Cohen、Jennifer L. Barlow、Vered Klinghofer、Jerry L. Wessale

  DOI：10.1021/jm00045a003

  日期：1994.9

  The aim of this study was the discovery of nonpeptide renin inhibitors with much improved oral absorption, bioavailability, and efficacy, for use as antihypertensive agents. Our prior efforts led to the identification of A-74273 [1, R = 3-(4-morpholino)propyl], with a bioavailability of 26 +/- 10% [10 mg/kg intraduodenally (id), dog]. In vivo metabolism studies of A-74273 showed that the morpholino moiety underwent metabolic degradation. Computer modeling of A-74273 bound to renin indicated that the C-terminus was involved in a hydrogen-bonding network. New C-terminal groups were examined in two series of nonpeptides for effects on renin binding potency, lipophilicity (log P), and aqueous solubility. Those groups which possessed multiple hydrogen-bonding ability (3,5-diaminotriazole, cyanoguanidines, morpholino) provided particularly potent renin binding. Intraduodenal bioavailabilities of selected compounds, evaluated in rats, ferrets, and dogs, were higher for inhibitors with moderate solubility as well as moderate lipophilicity, in general. Although the absolute values varied substantially among species, the relative ordering of the inhibitors in terms of absorption and bioavailablity was reasonably consistent. Such well absorbed inhibitors (e.g. 41, 44, and 51) were demonstrated as highly efficacious hypotensive agents in the salt-depleted dog. We report here the discovery of a series of efficacious nonpeptide renin inhibitors based on the 3-azaglutaramide P-2-P-4 replacement, the best of which showed id bioavailabilities > 50% in dog.