(2R,4S,5S,7S)-3-{5-tert-butoxycarbonylamino-4-hydroxy-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-2,8-dimethyl-nonanoylamino}-propionic acid ethyl ester | 173337-89-8

• 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: (2R,4S,5S,7S)-3-{5-tert-butoxycarbonylamino-4-hydroxy-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-2,8-dimethyl-nonanoylamino}-propionic acid ethyl ester
• 英文别名: 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoic acid N-(2-ethoxycarbonylethyl) amide；ethyl 3-[[(2R,4S,5S,7S)-4-hydroxy-7-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-2,8-dimethyl-5-[(2-methylpropan-2-yl)oxycarbonylamino]nonanoyl]amino]propanoate
• CAS: 173337-89-8
• 化学式: C₃₃H₅₆N₂O₉
• 分子量: 624.816
• InChiKey: QTKLAEWJCMXASH-BDGPUAICSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  44
• 可旋转键数：
  23
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  142
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (2R,4S,5S,7S)-3-{5-tert-butoxycarbonylamino-4-hydroxy-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-2,8-dimethyl-nonanoylamino}-propionic acid ethyl ester 在 sodium hydroxide 、 水 作用下， 以 甲醇 为溶剂， 反应 18.0h， 生成 (2R,4S,5S,7S)-3-{5-tert-butoxycarbonylamino-4-hydroxy-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-2,8-dimethyl-nonanoylamino}-propionic acid
  参考文献：
  名称：

  [EN] METHODS OF TREATING ALZHEIMER'S DISEASE USING ARYL ALKANOIC ACID AMIDES
  [FR] METHODES DE TRAITEMENT DE LA MALADIE D'ALZHEIMER PAR DES AMIDES D'ACIDE ARYL ALCANOIQUE

  摘要：

  揭示了一种治疗阿尔茨海默病和其他疾病，和/或抑制β-分泌酶，和/或通过使用式1（1）中定义的化合物在哺乳动物体内抑制Aβ肽的沉积的方法。其中变量R1-R8和X在此处定义。

  公开号：

  WO2003103653A1
• 作为产物：
  描述：

  (2R,4S,5S,7S)-3-{5-tert-butoxycarbonylamino-4-(tert-butyl-dimethyl-silanyloxy)-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-2,8-dimethyl-nonanylamino}-propionic acid ethyl ester 在 tetrabutyl-ammonium-fluoride trihydrate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 以80%的产率得到(2R,4S,5S,7S)-3-{5-tert-butoxycarbonylamino-4-hydroxy-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-2,8-dimethyl-nonanoylamino}-propionic acid ethyl ester
  参考文献：
  名称：

  Novel 2,7-Dialkyl-Substituted 5(S)-Amino-4(S)-hydroxy-8-phenyl-octanecarboxamide Transition State Peptidomimetics Are Potent and Orally Active Inhibitors of Human Renin

  摘要：

  The action of renin is the rate-limiting step of the renin-angiotensin system (RAS), a key regulator of blood pressure. Effective renin inhibitors directly block the RAS entirely at source and, thus, may provide a vital weapon for hypertension therapy. Our efforts toward identifying novel small-molecule peptidomimetic renin inhibitors have resulted in the design of transition-state isosteres such as I bearing an all-carbon 8-phenyl-octanecarboxamide framework. Optimization of the extended P3 portion of I and extensive P2' modifications provided analogues with improved in vitro potencies in the presence of plasma. X-ray resolution of rhrenin/38a in the course of SAR work surprisingly unveiled the exploitation of a previously unexplored pocket (S3(SP)) important for strong binding affinities. Several inhibitors demonstrated oral efficacy in sodium-depleted marmosets. The most potent, 38a, induced dose-dependently a pronounced reduction in mean arterial blood pressure, paralleled by complete blockade of active plasma renin, up to 8 h post-dose. Oral bioavailability of 38a was 16% in marmosets.

  DOI：

  10.1021/jm070314y

文献信息

• [EN] METHODS OF TREATING ALZHEIMER'S DISEASE USING ARYL ALKANOIC ACID AMIDES<br/>[FR] METHODES DE TRAITEMENT DE LA MALADIE D'ALZHEIMER PAR DES AMIDES D'ACIDE ARYL ALCANOIQUE
  申请人：ELAN PHARM INC

  公开号：WO2003103653A1

  公开（公告）日：2003-12-18

  Disclosed are methods for treating Alzheimer’s disease, and other diseases, and/or inhibiting beta-secretase enzyme, and/or inhibiting deposition of A beta peptide in a mammal, by use of compounds of formula 1 (1) wherein the variables R1-R8 and X are defined herein.

  揭示了一种治疗阿尔茨海默病和其他疾病，和/或抑制β-分泌酶，和/或通过使用式1（1）中定义的化合物在哺乳动物体内抑制Aβ肽的沉积的方法。其中变量R1-R8和X在此处定义。
• Novel 2,7-Dialkyl-Substituted 5(<i>S</i>)-Amino-4(<i>S</i>)-hydroxy-8-phenyl-octanecarboxamide Transition State Peptidomimetics Are Potent and Orally Active Inhibitors of Human Renin
  作者：Richard Göschke、Stefan Stutz、Vittorio Rasetti、Nissim-Claude Cohen、Joseph Rahuel、Pascal Rigollier、Hans-Peter Baum、Peter Forgiarini、Christian R. Schnell、Trixie Wagner、Markus G. Gruetter、Walter Fuhrer、Walter Schilling、Frédéric Cumin、Jeanette M. Wood、Jürgen Maibaum

  DOI：10.1021/jm070314y

  日期：2007.10.1

  The action of renin is the rate-limiting step of the renin-angiotensin system (RAS), a key regulator of blood pressure. Effective renin inhibitors directly block the RAS entirely at source and, thus, may provide a vital weapon for hypertension therapy. Our efforts toward identifying novel small-molecule peptidomimetic renin inhibitors have resulted in the design of transition-state isosteres such as I bearing an all-carbon 8-phenyl-octanecarboxamide framework. Optimization of the extended P3 portion of I and extensive P2' modifications provided analogues with improved in vitro potencies in the presence of plasma. X-ray resolution of rhrenin/38a in the course of SAR work surprisingly unveiled the exploitation of a previously unexplored pocket (S3(SP)) important for strong binding affinities. Several inhibitors demonstrated oral efficacy in sodium-depleted marmosets. The most potent, 38a, induced dose-dependently a pronounced reduction in mean arterial blood pressure, paralleled by complete blockade of active plasma renin, up to 8 h post-dose. Oral bioavailability of 38a was 16% in marmosets.