tert-butyl 3-allyloxy4-((6-(benzyl(tert-butoxycarbonyl)amino)-4-methylpyridin-2-yl)methyl)pyrrolidine-1-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: tert-butyl 3-allyloxy4-((6-(benzyl(tert-butoxycarbonyl)amino)-4-methylpyridin-2-yl)methyl)pyrrolidine-1-carboxylate
• 英文别名: (+/-)-cis-tert-butyl 3-allyloxy-4-{{6-[(benzyl)(tert-butoxycarbonyl)amino]-4-methyl-pyridin-2-yl}methyl}pyrrolidine-1-carboxylate；tert-butyl (3R,4R)-3-[[6-[benzyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]-4-methylpyridin-2-yl]methyl]-4-prop-2-enoxypyrrolidine-1-carboxylate
• 化学式: C₃₁H₄₃N₃O₅
• 分子量: 537.7
• InChiKey: ORLNYHHCAWSRDM-RSXGOPAZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  39
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  81.2
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  tert-butyl 3-allyloxy4-((6-(benzyl(tert-butoxycarbonyl)amino)-4-methylpyridin-2-yl)methyl)pyrrolidine-1-carboxylate 在 臭氧 、 锌 作用下， 反应 2.0h， 以81%的产率得到tert-butyl 3-((6-(benzyl(tert-butoxycarbonyl)amino)-4-methylpyridin-2-yl)methyl)-4-(2-oxoethyl)pyrrolidine-1-carboxylate
  参考文献：
  名称：

  神经元一氧化氮合酶的强效、高选择性和口服生物可利用的宝石二氟化单阳离子抑制剂

  摘要：

  在我们努力发现神经元异构体选择性一氧化氮合酶 (NOS) 抑制剂的过程中，我们开发了一系列含有具有两个立体中心的吡咯烷环的化合物。对映体纯化合物（S，S）与（R，R）表现出两种不同的结合方向，（R，R）抑制剂显示出更好的效力和选择性。为了提高这些抑制剂的生物利用度，我们在这些抑制剂之一的长尾中的氨基中引入了 CF(2) 基团，这降低了其碱性，导致在生理 pH 条件下具有单阳离子特性的化合物。生物学评估导致了一种 nNOS 抑制剂，其 K(i) 为 36 nM，对 nNOS 的选择性高于 eNOS（3800 倍）和 iNOS（1400 倍）。MM-PBSA 计算表明，低 pK(a) NH 至少是，当与活性位点结合时部分质子化。二氟化化合物与母体分子的大鼠口服生物利用度的比较显示，二氟化化合物为22%，而母体化合物的口服生物利用度基本为零。这表明，本研究的目标是制造在生理 pH 值下仅具有一个

  DOI：

  10.1021/ja106175q
• 作为产物：
  描述：

  溴甲苯 在 甲醇 、 sodium hydroxide 、 偶氮二甲酸二异丙酯 、 水 、 sodium hydride 、 三苯基膦 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 生成 tert-butyl 3-allyloxy4-((6-(benzyl(tert-butoxycarbonyl)amino)-4-methylpyridin-2-yl)methyl)pyrrolidine-1-carboxylate
  参考文献：
  名称：

  WO2008/42353

  摘要：

  公开号：

文献信息

• Potent and highly selective heteroaromatic inhibitors of neuronal nitric oxide synthase
  申请人：Silverman B. Richard

  公开号：US20080108814A1

  公开（公告）日：2008-05-08

  Peptidomimetic compounds as can inhibit neuronal nitric oxide synthase (nNOS) for potential treatment in neurodegenerative diseases, such as but not limited to stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease.

  肽类类似物化合物可抑制神经元一氧化氮合酶(nNOS)，用于潜在的治疗神经退行性疾病，如中风、阿尔茨海默病、帕金森病、亨廷顿病等。
• Exploration of the Active Site of Neuronal Nitric Oxide Synthase by the Design and Synthesis of Pyrrolidinomethyl 2-Aminopyridine Derivatives
  作者：Haitao Ji、Silvia L. Delker、Huiying Li、Pavel Martásek、Linda J. Roman、Thomas L. Poulos、Richard B. Silverman

  DOI：10.1021/jm100947x

  日期：2010.11.11

  Neuronal nitric oxide synthase (nNOS) represents an important therapeutic target for the prevention of brain injury and the treatment of various neurodegenerative disorders. A series of trans-substituted amino pyrrolidinomethyl 2-aminopyridine derivatives (8-34) was designed and synthesized. A structure activity relationship analysis led to the discovery of low nanomolar nNOS inhibitors ((+/-)-32 and (+/-)-34) with more than 1000-fold selectivity for nNOS over eNOS. Four enantiomerically pure isomers of 3'-[2 ''-(3 ''-fluorophenethylamino)ethoxy]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine (4) also were synthesized. It was found that (3'R,4'R)-4 can induce enzyme elasticity to generate a new "hot spot" for ligand binding. The inhibitor adopts a unique binding mode, the same as that observed for (3'R,4'R)-3'-[2 ''-(3'''-fluorophenethylamino)ethylamino]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine ((3'R,4'R)-3) (J. Am. Chem. Soc. 2010, 132 (15), 5437-5442). On the basis of structure-activity relationships of 8-34 and different binding conformations of the cis and trans isomers of 3 and 4, critical structural requirements of the NOS active site for ligand binding are revealed.
• Effect of potential amine prodrugs of selective neuronal nitric oxide synthase inhibitors on blood–brain barrier penetration
  作者：Richard B. Silverman、Graham R. Lawton、Hantamalala Ralay Ranaivo、Laura K. Chico、Jiwon Seo、D. Martin Watterson

  DOI：10.1016/j.bmc.2009.08.065

  日期：2009.11

  Several prodrug approaches were taken to mask amino groups in two potent and selective neuronal nitric oxide synthase (nNOS) inhibitors containing either a primary or secondary amino group to lower the charge and improve blood-brain barrier (BBB) penetration. The primary amine was masked as an azide and the secondary amine as an amide or carbamate. The azide was not reduced to the amine under a variety of in vitro and ex vivo conditions. Despite the decrease in charge of the amino group as an amide and as carbamates, BBB penetration did not increase. It appears that the uses of azides as prodrugs for primary amines or amides and carbamates as prodrugs for secondary amines are not universally effective for CNS applications. (C) 2009 Elsevier Ltd. All rights reserved.
• Analogues of 2-aminopyridine-based selective inhibitors of neuronal nitric oxide synthase with increased bioavailability
  作者：Graham R. Lawton、Hantamalala Ralay Ranaivo、Laura K. Chico、Haitao Ji、Fengtian Xue、Pavel Martásek、Linda J. Roman、D. Martin Watterson、Richard B. Silverman

  DOI：10.1016/j.bmc.2009.02.017

  日期：2009.3

  Overproduction of nitric oxide by neuronal nitric oxide synthase ( nNOS) has been linked to several neurodegenerative diseases. We have recently designed potent and isoform selective inhibitors of nNOS, but the lead compound contains several basic functional groups. A large number of charges and hydrogen bond donors can impede the ability of molecules to cross the blood brain barrier and thereby limit the effectiveness of potential neurological therapeutics. Replacement of secondary amines in our lead compound with neutral ether and amide groups was made to increase bioavailability and to determine if the potency and selectivity of the inhibitor would be impacted. An ether analogue has been identified that retains a similar potency and selectivity to that of the lead compound, and shows increased ability to penetrate the blood brain barrier. (C) 2009 Elsevier Ltd. All rights reserved.
• Selective Neuronal Nitric Oxide Synthase Inhibitors
  申请人：Silverman Richard B.

  公开号：US20120258513A1

  公开（公告）日：2012-10-11

  Compounds and related methods for selective inhibition of neuronal nitric oxide synthase over inducible and endothelial isoforms, such compounds as can provide reduced cationic character and enhanced bioavailability.