N-[(1S,2R)-2-hydroxy-3-[((2S)-2-methylbutyl)amino]-1-(phenylmethyl)propyl]-carbamic acid 1,1-dimethylethyl ester | 1026701-65-4

• 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: N-[(1S,2R)-2-hydroxy-3-[((2S)-2-methylbutyl)amino]-1-(phenylmethyl)propyl]-carbamic acid 1,1-dimethylethyl ester
• 英文别名: tert-butyl ((2S,3R)-3-hydroxy-4-(((2S)-2-methylbutyl)amino)-1-phenylbutan-2-yl)carbamate；tert-butyl ((2S,3R)-3-hydroxy-4-(((S)-2-methylbutyl)amino)-1-phenylbutan-2-yl)carbamate
• CAS: 1026701-65-4
• 化学式: C₂₀H₃₄N₂O₃
• 分子量: 350.502
• InChiKey: UQMOPFSKRIQTON-RYQLBKOJSA-N

物化性质

• 沸点：
  496.4±45.0 °C(Predicted)
• 密度：
  1.030±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.12
• 重原子数：
  25.0
• 可旋转键数：
  9.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  70.59
• 氢给体数：
  3.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  N-[(1S,2R)-2-hydroxy-3-[((2S)-2-methylbutyl)amino]-1-(phenylmethyl)propyl]-carbamic acid 1,1-dimethylethyl ester 在 sodium carbonate 、 三氟乙酸 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 6.0h， 生成 N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-4-methoxy-N-((S)-2-methylbutyl)benzenesulfonamide
  参考文献：
  名称：

  用于对抗耐药性的新型 HIV-1 蛋白酶抑制剂的设计、合成以及生物学和结构评估

  摘要：

  一系列新的 HIV-1 蛋白酶抑制剂 (PI) 是使用一种通用策略设计的，该策略将基于计算结构的设计与底物包络约束相结合。PI 将具有无环和环状杂原子官能团的各种醇衍生的 P2 氨基甲酸酯结合到 ( R )-羟乙胺等排体中。大多数新的 PI 显示出对野生型 HIV-1 蛋白酶和三种多重耐药 (MDR) 变体的有效结合亲和力。特别是，含有 2,2-二氯乙酰胺、吡咯烷酮、咪唑烷酮和 恶唑烷酮部分的抑制剂在 P2 处对K i最有效皮摩尔范围内的值。几种新的 PI 对来自 HIV-1 进化枝 A、B 和 C 以及两种 MDR 变体的患者来源的野生型病毒表现出纳摩尔级的抗病毒效力。四种有效抑制剂的晶体结构分析表明，新 P2 部分的羰基促进了与蛋白酶不变的 Asp29 残基的广泛氢键相互作用。这些构效关系的发现可用于设计具有增强的酶抑制和抗病毒效力的新 PI。

  DOI：

  10.1021/jm300238h
• 作为产物：
  描述：

  (S)-(-)-2-甲基丁胺 、 1-苄基-2,3-环氧正丙基-氨基甲酸叔丁酯 以 乙醇 为溶剂， 反应 3.0h， 以87%的产率得到N-[(1S,2R)-2-hydroxy-3-[((2S)-2-methylbutyl)amino]-1-(phenylmethyl)propyl]-carbamic acid 1,1-dimethylethyl ester
  参考文献：
  名称：

  整合了立体化学定义的P2'配体的HIV-1蛋白酶抑制剂可优化底物信封中的氢键。

  摘要：

  结构导向的设计策略用于通过优化氢键和范德华与蛋白酶的相互作用，同时保留在底物包膜内来改善HIV-1蛋白酶抑制剂的抗药性。探索了4-（1-羟乙基）苯和4-（1,2-二羟乙基）苯部分的立体异构体，作为P2'配体，在P2'提供了一对非对映异构体差向异构体，这些异构体根据羟基的构型表现出不同的效能曲线和P1'组的大小。尽管具有4-（1-羟乙基）苯P2'部分的化合物对一组具有多重耐药性的HIV-1菌株保持了出色的抗病毒效力，但具有极性4-（1,2-二羟乙基）苯部分的类似物的效力较弱，并且只有（R）-受体具有更大的2-乙基丁基P1' 组显示出增强的效力。蛋白酶抑制剂复合物的晶体结构显示羟乙基的（R）-和（S）-立体异构体与Asp30'的强氢键相互作用。值得注意的是，（R）-二羟乙基参与与Asp29′和Asp30′的主链酰胺直接氢键相互作用的独特模式。SAR数据和晶体结构分析为优化这些有前途的HIV-1蛋白酶抑制剂提供了见识。

  DOI：

  10.1021/acs.jmedchem.9b00838

文献信息

• Substrate Envelope-Designed Potent HIV-1 Protease Inhibitors to Avoid Drug Resistance
  作者：Madhavi N.L. Nalam、Akbar Ali、G.S. Kiran Kumar Reddy、Hong Cao、Saima G. Anjum、Michael D. Altman、Nese Kurt Yilmaz、Bruce Tidor、Tariq M. Rana、Celia A. Schiffer

  DOI：10.1016/j.chembiol.2013.07.014

  日期：2013.9

  The rapid evolution of HIV under selective drug pressure has led to multidrug resistant (MDR) strains that evade standard therapies. We designed highly potent HIV-1 protease inhibitors (Pis) using the substrate envelope model, which confines inhibitors within the consensus volume of natural substrates, providing inhibitors less susceptible to resistance because a mutation affecting such inhibitors will simultaneously affect viral substrate processing. The designed Pis share a common chemical scaffold but utilize various moieties that optimally fill the substrate envelope, as confirmed by crystal structures. The designed Pis retain robust binding to MDR protease variants and display exceptional antiviral potencies against different clades of HIV as well as a panel of 12 drug-resistant viral strains. The substrate envelope model proves to be a powerful strategy to develop potent and robust inhibitors that avoid drug resistance.
• HIV-1 Protease Inhibitors from Inverse Design in the Substrate Envelope Exhibit Subnanomolar Binding to Drug-Resistant Variants
  作者：Michael D. Altman、Akbar Ali、G. S. Kiran Kumar Reddy、Madhavi N. L. Nalam、Saima Ghafoor Anjum、Hong Cao、Sripriya Chellappan、Visvaldas Kairys、Miguel X. Fernandes、Michael K. Gilson、Celia A. Schiffer、Tariq M. Rana、Bruce Tidor

  DOI：10.1021/ja076558p

  日期：2008.5.1

  The acquisition of drug-resistant mutations by infectious pathogens remains a pressing health concern, and the development of strategies to combat this threat is a priority. Here we have applied a general strategy, inverse design using the substrate envelope, to develop inhibitors of HIV-1 protease. Structure-based computation was used to design inhibitors predicted to stay within a consensus substrate volume in the binding site. Two rounds of design, synthesis, experimental testing, and structural analysis were carried out, resulting in a total of 51 compounds. Improvements in design methodology led to a roughly 1000-fold affinity enhancement to a wild-type protease for the best binders, from a K(i) of 30-50 nM in round one to below 100 pM in round two. Crystal structures of a subset of complexes revealed a binding mode similar to each design that respected the substrate envelope in nearly all cases. All four best binders from round one exhibited broad specificity against a clinically relevant panel of drug-resistant HIV-1 protease variants, losing no more than 6-13-fold affinity relative to wild type. Testing a subset of second-round compounds against the panel of resistant variants revealed three classes of inhibitors: robust binders (maximum affinity loss of 14-16-fold), moderate binders (35-80-fold), and susceptible binders (greater than 100-fold). Although for especially high-affinity inhibitors additional factors may also be important, overall, these results suggest that designing inhibitors using the substrate envelope may be a useful strategy in the development of therapeutics with low susceptibility to resistance.
• Additivity in the Analysis and Design of HIV Protease Inhibitors
  作者：Robert N. Jorissen、G. S. Kiran Kumar Reddy、Akbar Ali、Michael D. Altman、Sripriya Chellappan、Saima G. Anjum、Bruce Tidor、Celia A. Schiffer、Tariq M. Rana、Michael K. Gilson

  DOI：10.1021/jm8009525

  日期：2009.2.12

  We explore the applicability of an additive treatment of substituent effects to the analysis and design of HIV protease inhibitors. Affinity data for a set of inhibitors with a common chemical framework were analyzed to provide estimates of the free energy contribution of each chemical substituent. These estimates were then used to design new inhibitors whose high affinities were confirmed by synthesis and experimental testing. Derivations of additive models by least-squares and ridge-regression methods were found to yield statistically similar results. The additivity approach was also compared with standard molecular descriptor-based QSAR; the latter was not found to provide superior predictions. Crystallographic studies of HIV protease-inhibitor complexes help explain the perhaps surprisingly high degree of substituent additivity in this system, and allow some of the additivity coefficients to be rationalized on a structural basis.
• WO2008/118849
  申请人：——

  公开号：——

  公开（公告）日：——