3-fluoro-N-[(1S,2R)-2-hydroxy-3-[[(3-methoxyphenyl)sulfonyl](2-thienylmethyl)amino]-1-(phenylmethyl)propyl]-2-methyl-benzamide

• 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: 3-fluoro-N-[(1S,2R)-2-hydroxy-3-[[(3-methoxyphenyl)sulfonyl](2-thienylmethyl)amino]-1-(phenylmethyl)propyl]-2-methyl-benzamide
• 英文别名: N-[(1s,2r)-1-Benzyl-2-Hydroxy-3-{[(3-Methoxyphenyl)sulfonyl](2-Thienylmethyl)amino}propyl]-3-Fluoro-2-Methylbenzamide；3-fluoro-N-[(2S,3R)-3-hydroxy-4-[(3-methoxyphenyl)sulfonyl-(thiophen-2-ylmethyl)amino]-1-phenylbutan-2-yl]-2-methylbenzamide
• 化学式: C₃₀H₃₁FN₂O₅S₂
• 分子量: 582.717
• InChiKey: AXUYLLZCOSCKTG-URLMMPGGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  40
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  133
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-3-methoxy-N-(thiophen-2-ylmethyl)benzenesulfonamide 、 3-氟-2-甲基苯甲酸 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0.250 g的产率得到3-fluoro-N-[(1S,2R)-2-hydroxy-3-[[(3-methoxyphenyl)sulfonyl](2-thienylmethyl)amino]-1-(phenylmethyl)propyl]-2-methyl-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

文献信息

• 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.