N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzo[d]thiazole-6-sulfonamide | 656236-30-5

• 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-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzo[d]thiazole-6-sulfonamide
• 英文别名: Benzothiazole-6-sulfonic acid ((2R,3S)-3-amino-2-hydroxy-4-phenyl-butyl)-isobutyl-amide；N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)-1,3-benzothiazole-6-sulfonamide
• CAS: 656236-30-5
• 化学式: C₂₁H₂₇N₃O₃S₂
• 分子量: 433.596
• InChiKey: LXZASRSSTBFAOR-AZUAARDMSA-N

物化性质

• 沸点：
  634.4±65.0 °C(Predicted)
• 密度：
  1.298±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  29
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  133
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  间羟基苯甲酸 、 N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzo[d]thiazole-6-sulfonamide 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 以0.218 g的产率得到N-[(1S,2R)-3-[(6-benzothiazolylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-3-hydroxy-benzamide
  参考文献：
  名称：

  HIV-1 Protease Inhibitors from Inverse Design in the Substrate Envelope Exhibit Subnanomolar Binding to Drug-Resistant Variants

  摘要：

  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.

  DOI：

  10.1021/ja076558p
• 作为产物：
  描述：

  [(1S,2R)-1-苄基-1-苄氧羰基氨基-2-羟基-4-N-异丁基氨基丙烷 在 palladium on activated charcoal 盐酸 、 氢气 、 copper(II) sulfate 、 三乙胺 、 亚硝酸异戊酯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 38.0h， 生成 N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzo[d]thiazole-6-sulfonamide
  参考文献：
  名称：

  Discovery of novel benzothiazolesulfonamides as potent inhibitors of HIV-1 protease

  摘要：

  The human immunodeficiency virus (HIV) has been shown to be the causative agent for AIDS. The HIV virus encodes for a unique aspartyl protease that is essential for the production of enzymes and proteins in the final stages of maturation. Protease inhibitors have been useful in combating the disease. The inhibitors incorporate a variety of isosteres including the hydroxy-ethylurea at the protease cleavage site. We have shown that the replacement of t-butylurea moiety by benzothiazolesulfonamide provided inhibitors with improved potency and antiviral activities. Some of the compounds have shown good oral bioavailability and half-life in rats. The synthesis of benzothiazole derivatives led us to explore other heterocycles. During the course of our Studies. we also developed an efficient synthesis of benzothiazole-6-sulfonic acid via a two-step procedure starting from sulfanilamide. (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2003.07.001

文献信息

• Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
  申请人：Getman P. Daniel

  公开号：US20070004646A1

  公开（公告）日：2007-01-04

  Selected heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to such retroviral protease inhibitors and, more particularly, relates to selected novel compounds, compositions, and methods for inhibiting retroviral proteases, such as human immunodeficiency virus (HIV) protease, prophylactically preventing retroviral infection or the spread of a retrovirus, and treatment of a retroviral infection.

  选择性杂环羰基氨基酸羟乙基氨磺酰胺化合物可作为逆转录病毒蛋白酶抑制剂，特别是作为HIV蛋白酶抑制剂。本发明涉及这种逆转录病毒蛋白酶抑制剂，更具体地涉及选择性新化合物、组合物和方法，用于抑制逆转录病毒蛋白酶，如人类免疫缺陷病毒（HIV）蛋白酶，预防逆转录病毒感染或逆转录病毒的传播，并治疗逆转录病毒感染。
• BIS-AMINO ACID HYDROXYETHYLAMINO SULFONAMIDE RETROVIRAL PROTEASE INHIBITORS
  申请人：Getman P. Daniel

  公开号：US20080118969A1

  公开（公告）日：2008-05-22

  Selected bis-amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to such retroviral protease inhibitors and, more particularly, relates to selected novel compounds, compositions, and methods for inhibiting retroviral proteases, such as human immunodeficiency virus (HIV) protease, prophylactically preventing retroviral infection or the spread of a retrovirus, and treatment of a retroviral infection.

  选择性的双氨基酸羟乙基氨磺酰胺类化合物在逆转录病毒蛋白酶抑制剂中具有有效性，尤其是在HIV蛋白酶抑制剂中具有有效性。本发明涉及这种逆转录病毒蛋白酶抑制剂，更具体地涉及选择性的新化合物、组合物和方法，用于抑制逆转录病毒蛋白酶，如人类免疫缺陷病毒（HIV）蛋白酶，预防逆转录病毒感染或逆转录病毒的传播，以及治疗逆转录病毒感染。
• Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
  申请人：Getman P. Daniel

  公开号：US20070037754A1

  公开（公告）日：2007-02-15

  Selected bis-amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to such retroviral protease inhibitors and, more particularly, relates to selected novel compounds, compositions, and methods for inhibiting retroviral proteases, such as human inmmunodeficiency virus (HIV) protease, prophylactically preventing retroviral infection or the spread of a retrovirus, and treatment of a retroviral infection.

  选择性的双氨基酸羟乙基氨磺酰胺化合物被证明是反转录病毒蛋白酶抑制剂，特别是HIV蛋白酶的抑制剂。本发明涉及这种反转录病毒蛋白酶抑制剂，更具体地涉及选定的新化合物、组合物和方法，用于抑制反转录病毒蛋白酶，例如人类免疫缺陷病毒（HIV）蛋白酶，预防反转录病毒感染或反转录病毒的传播，以及治疗反转录病毒感染。
• 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.
• US7161033B2
  申请人：——

  公开号：US7161033B2

  公开（公告）日：2007-01-09