(R)-N-(2-methylbenzyl)-3-[(2S,3S)-3-((S)-2-(isoquinolin-5-yloxyacetyl)amino-2-((R)-tetrahydrofuran-3-yl)acetyl)amino-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (R)-N-(2-methylbenzyl)-3-[(2S,3S)-3-((S)-2-(isoquinolin-5-yloxyacetyl)amino-2-((R)-tetrahydrofuran-3-yl)acetyl)amino-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide
• 英文别名: KNI-1641；(4R)-3-[(2S,3S)-2-hydroxy-3-[[(2S)-2-[[2-(5-isoquinolyloxy)acetyl]amino]-2-[(3R)-tetrahydrofuran-3-yl]acetyl]amino]-4-phenyl-butanoyl]-5,5-dimethyl-N-(o-tolylmethyl)thiazolidine-4-carboxamide；(4R)-3-[(2S,3S)-2-hydroxy-3-[[(2S)-2-[(2-isoquinolin-5-yloxyacetyl)amino]-2-[(3R)-oxolan-3-yl]acetyl]amino]-4-phenylbutanoyl]-5,5-dimethyl-N-[(2-methylphenyl)methyl]-1,3-thiazolidine-4-carboxamide
• 化学式: C₄₁H₄₇N₅O₇S
• 分子量: 753.919
• InChiKey: AGTXOBBDJQMXGV-ANTFRMDBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  54
• 可旋转键数：
  14
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  185
• 氢给体数：
  4
• 氢受体数：
  9

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  ——	Boc-Apns-Dmt-NH(o-methylbenzyl)	478699-59-1	C29H39N3O5S	541.712

反应信息

• 作为产物：
  描述：

  Boc-Apns-Dmt-NH(o-methylbenzyl) 在 盐酸 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 1-羟基苯并三唑 、 苯甲醚 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 29.0h， 生成 (R)-N-(2-methylbenzyl)-3-[(2S,3S)-3-((S)-2-(isoquinolin-5-yloxyacetyl)amino-2-((R)-tetrahydrofuran-3-yl)acetyl)amino-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide
  参考文献：
  名称：

  Identification of Highly Potent Human Immunodeficiency Virus Type-1 Protease Inhibitors against Lopinavir and Darunavir Resistant Viruses from Allophenylnorstatine-Based Peptidomimetics with P2 Tetrahydrofuranylglycine

  摘要：

  The emergence of drug-resistant HIV from a widespread antiviral chemotherapy targeting HIV protease in the past decades is unavoidable and provides a challenge to develop alternative inhibitors. We synthesized a series of allophenylnorstatine-based peptidomimetics with various P-3, P-2, and P-2' moieties. The derivatives with P-2 tetrahydrofur-anylglycine (Thfg) were found to be potent against wild type HIV-1 protease and the virus, leading to a highly potent compound 21f (KNI-1657) against lopinavir/ritonavir- or darunavir-resistant strains. Co-crystal structures of 21f and the wild-type protease revealed numerous key hydrogen bonding interactions with Thfg. These results suggest that the strategy to design allophenylnorstatine-based peptidomimetics combined with Thfg residue would be promising for generating candidates to overcome multidrug resistance.

  DOI：

  10.1021/acs.jmedchem.7b01709

文献信息

• Identification of Highly Potent Human Immunodeficiency Virus Type-1 Protease Inhibitors against Lopinavir and Darunavir Resistant Viruses from Allophenylnorstatine-Based Peptidomimetics with P2 Tetrahydrofuranylglycine
  作者：Koushi Hidaka、Tooru Kimura、Rajesh Sankaranarayanan、Jun Wang、Keith F. McDaniel、Dale J. Kempf、Masanori Kameoka、Motoyasu Adachi、Ryota Kuroki、Jeffrey-Tri Nguyen、Yoshio Hayashi、Yoshiaki Kiso

  DOI：10.1021/acs.jmedchem.7b01709

  日期：2018.6.28

  The emergence of drug-resistant HIV from a widespread antiviral chemotherapy targeting HIV protease in the past decades is unavoidable and provides a challenge to develop alternative inhibitors. We synthesized a series of allophenylnorstatine-based peptidomimetics with various P-3, P-2, and P-2' moieties. The derivatives with P-2 tetrahydrofur-anylglycine (Thfg) were found to be potent against wild type HIV-1 protease and the virus, leading to a highly potent compound 21f (KNI-1657) against lopinavir/ritonavir- or darunavir-resistant strains. Co-crystal structures of 21f and the wild-type protease revealed numerous key hydrogen bonding interactions with Thfg. These results suggest that the strategy to design allophenylnorstatine-based peptidomimetics combined with Thfg residue would be promising for generating candidates to overcome multidrug resistance.