<3S-<3α,5β(R^*)>>-5-(2-Cyclohexyl-1-aminoethyl)dihydro-3-isopropyl-2(3H)-furanone | 125816-10-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酯类
• 英文名称: <3S-<3α,5β(R^*)>>-5-(2-Cyclohexyl-1-aminoethyl)dihydro-3-isopropyl-2(3H)-furanone
• 英文别名: (2S,4S,5S)-5 Amino-6-cyclohexyl-4-hydroxy-2-isopropyl hexanoic acid lactone；(3S,5S,1'S)-5-(1-amino-2-cyclohexylethyl)-3-isopropyltetrahydrofuran-2-one；(2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid lactone；(3S,5S)-5-[(1S)-1-amino-2-cyclohexylethyl]-3-propan-2-yloxolan-2-one
• CAS: 125816-10-6
• 化学式: C₁₅H₂₇NO₂
• 分子量: 253.385
• InChiKey: RIJKESWRYNDYGY-IHRRRGAJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  18
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.93
• 拓扑面积：
  52.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  <3S-<3α,5β(R^*)>>-5-(2-Cyclohexyl-1-aminoethyl)dihydro-3-isopropyl-2(3H)-furanone 在 二甲基氯化铝 、 1-羟基苯并三唑一水物 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 正己烷 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 (2S,4S,5S)-N-butyl-6-cyclohexyl-4-hydroxy-N-methyl-2-propan-2-yl-5-[[2-(8-propyl-6-pyridin-3-yl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3-pyridin-3-ylpropanoyl]amino]hexanamide
  参考文献：
  名称：

  1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 2. Synthesis, biological properties and molecular modeling of hydroxyethylene isostere derivatives

  摘要：

  A series of inhibitors of human renin have been synthesized, derived from combination of a 2-(8-propyl-6-pyridin-3-yl-1,2,4-triazolo[4,3-a]pyrazin-3-yl)- 3-pyridin- 3-ylpropionic acid moiety 6c with the hydroxyethylene isostere of the scissile amide bond (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid (ChaOH--Val). The more potent members of this series showed good inhibitory activity against partially purified human renin, 7d, for example, having an IC50 of 0.2 nM. Structure-activity relationships for these compounds were consistent with their binding to the S4-S2' sites of human renin. Analogues 7e and 7h-k with a variety of substituents at the C-terminus all had in vitro IC50S less than 1 nM. In contrast with the majority of previously reported inhibitors of similar potency, these compounds contain no natural amino acid fragments. When administered intravenously to anesthetized, sodium-depleted marmosets at doses of 0.3-3.0 mg/kg, compound 7d caused a marked reduction in mean arterial pressure. Following oral administration at 30 mg/kg in the same animal model, 7d again elicited a significant fall in mean arterial pressure, accompanied by suppression of plasma renin activity lasting up to 3 h after dosing.

  DOI：

  10.1021/jm00171a006
• 作为产物：
  描述：

  sodium 3-methyl-2-oxobutyrate 在 palladium on activated charcoal 盐酸 、 氢气 、 L-Selectride 、 碳酸氢钠 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 乙酸乙酯 为溶剂， 生成 <3S-<3α,5β(R^*)>>-5-(2-Cyclohexyl-1-aminoethyl)dihydro-3-isopropyl-2(3H)-furanone
  参考文献：
  名称：

  The stereospecific preparation of an hydroxyethylene isostere precursor via a novel piperidine-2,5-dione template

  摘要：

  Hydroxyethylene isostere precursor 2 was synthesized by stereochemical manipulation of a novel keto-lactam ''template''. The final product was prepared in very high enantiomeric purity, in 23% overall yield from L-phenylalanine.

  DOI：

  10.1016/s0040-4039(00)79750-4

文献信息

• Renin inhibitors
  申请人：Abbott Laboratories

  公开号：US05389647A1

  公开（公告）日：1995-02-14

  A renin inhibiting compound of the formula: ##STR1## wherein X is O, NH or S and G is a mimic of the Leu-Val cleavage site of angiotensinogen; or a pharmaceutically acceptable salt, ester or prodrug thereof; with the proviso that the compound is not N-(3-(4-Morpholino)propyl)-5(S)-(2(S)-(1(S)-(4-methoxymethoxy)piperidin-1- yl)carbonyl-2-phenyl)ethoxyhexanamido)-6-cyclohexyl-4(S)-hydroxy-2(S)-isopr opylhexanamide.

  化学式为：##STR1## 其中X为O、NH或S，G是模拟血管紧张素原的Leu-Val裂解位点；或其药用盐、酯或前药；但该化合物不是N-(3-(4-吗啉基)丙基)-5(S)-(2(S)-(1(S)-(4-甲氧甲氧基)哌啶-1-基)羧基-2-苯基)乙氧基己酰胺)-6-环己基-4(S)-羟基-2(S)-异丙基己酰胺。
• Synthesis of the lactone precursor to hydroxyethylene dipeptide isostere from 3,4,6-tri-O-acetyl-D-glucal
  作者：Masao Shiozaki、Tadashi Hata、Youji Furukawa

  DOI：10.1016/s0040-4039(01)80478-0

  日期：1989.1

  (2S,4S,5S)-5-Amino-6-cyclohexyl-4-hydroxy-2-isopropyl hexanoic acid lactone () was synthesized from 3,4,6-tri-O-acetyl-D-glucal in an efficient manner.

  （3S，4S，5S）-5-氨基-6-环己基-4-羟基-2-异丙基己酸内酯（）是由3,4,6-三-O-乙酰基-D-葡糖醛有效合成的。
• Synthesis of renin inhibitors possessing hydroxyethylene isostere residue from 3,4,6-tri-O-acetyl-D-qlucal via lactone precursor
  作者：Masao Shiozaki、Yoshiyuki Kobayashi、Tadashi Hata、Youji Furukawa

  DOI：10.1016/s0040-4020(01)87085-x

  日期：1991.1

  Syntheses of precursors for renin inhibitors possessing hydroxyethylene isostere residue from 2,4,6-tri--acetyl-D-glucal lactone precursor is described. This route makes it possible to synthesize analogues with various substituents at C-2 and C-5 of the hydroxyethylene isostere residue.

  描述了由2,4,6-三-乙酰基-D-葡萄糖醛酸内酯前体合成具有羟基亚乙基等排残基的肾素抑制剂的前体。该途径使得可以合成在羟乙烯等排残基的C-2和C-5处具有各种取代基的类似物。
• An efficient synthesis of the γ-lactone corresponding to a hydroxyethylene dipeptide isostere using stereoselective bromolactonisation of a chiral acyloxazolidinone
  作者：Robert H. Bradbury、John M. Revill、Janet E. Rivett、David Waterson

  DOI：10.1016/s0040-4039(01)80674-2

  日期：1989.1

  An efficient synthetic route is described to the γ-lactone corresponding to the dipeptide isostere (2,4,5)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid, in which stereochemical control is achieved by participation of chiral acyloxazolidinone in a stereoselective bromolactonisation reaction.

  一种有效的合成路线描述于γ内酯对应于二肽电子等排体（2 ，4 ，5 ）-5-氨基-6-环己基-4-羟基-2-异丙基己酸，其中立体化学控制是通过参与实现立体选择性溴内酯化反应中的手性酰基恶唑烷酮。
• 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.