(R)-N-[(1S,2R)-2-hydroxyindan-1-yl]-3-[(2S,3S)-3-(tert-butoxycarbonyl)amino-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide | 819805-78-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: (R)-N-[(1S,2R)-2-hydroxyindan-1-yl]-3-[(2S,3S)-3-(tert-butoxycarbonyl)amino-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide
• 英文别名: tert-butyl N-[(2S,3S)-3-hydroxy-4-[(4R)-4-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamoyl]-5,5-dimethyl-1,3-thiazolidin-3-yl]-4-oxo-1-phenylbutan-2-yl]carbamate
• CAS: 819805-78-2
• 化学式: C₃₀H₃₉N₃O₆S
• 分子量: 569.722
• InChiKey: OHHVHHQDQIXWKG-VMAPGKTHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  40
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  154
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (R)-N-[(1S,2R)-2-hydroxyindan-1-yl]-3-[(2S,3S)-3-(tert-butoxycarbonyl)amino-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide 在 盐酸 、 苯甲醚 作用下， 以 1,4-二氧六环 为溶剂， 生成 (R)-3-((2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl)-N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-5,5-dimethylthiazolidine-4-carboxamide
  参考文献：
  名称：

  Additional interaction of allophenylnorstatine-containing tripeptidomimetics with malarial aspartic protease plasmepsin II

  摘要：

  Based on a highly potent allophenylnorstatine-containing inhibitor, KNI-10006, against the plasmepsins of Plasmodium falciparum, we synthesized a series of tripeptide-type compounds with various N-terminal moieties and evaluated their inhibitory activities against plasmepsin II. Certain phenylacetyl derivatives exhibited extremely high affinity with Ki values of less than 0.1 nM suggesting successful hydrophobic interactions. (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.03.052
• 作为产物：
  描述：

  (1S,2R)-(-)-1-氨基-2-茚醇 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， 生成 (R)-N-[(1S,2R)-2-hydroxyindan-1-yl]-3-[(2S,3S)-3-(tert-butoxycarbonyl)amino-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide
  参考文献：
  名称：

  Additional interaction of allophenylnorstatine-containing tripeptidomimetics with malarial aspartic protease plasmepsin II

  摘要：

  Based on a highly potent allophenylnorstatine-containing inhibitor, KNI-10006, against the plasmepsins of Plasmodium falciparum, we synthesized a series of tripeptide-type compounds with various N-terminal moieties and evaluated their inhibitory activities against plasmepsin II. Certain phenylacetyl derivatives exhibited extremely high affinity with Ki values of less than 0.1 nM suggesting successful hydrophobic interactions. (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.03.052

文献信息

• Antimalarial activity enhancement in hydroxymethylcarbonyl (HMC) isostere-based dipeptidomimetics targeting malarial aspartic protease plasmepsin
  作者：Koushi Hidaka、Tooru Kimura、Adam J. Ruben、Tsuyoshi Uemura、Mami Kamiya、Aiko Kiso、Tetsuya Okamoto、Yumi Tsuchiya、Yoshio Hayashi、Ernesto Freire、Yoshiaki Kiso

  DOI：10.1016/j.bmc.2008.10.011

  日期：2008.12

  improve the antimalarial activity of peptidomimetic Plm inhibitors, we attached substituents on a structure of the highly potent Plm inhibitor KNI-10006. Among the derivatives, we identified alkylamino compounds such as 44 (KNI-10283) and 47 (KNI-10538) with more than 15-fold enhanced antimalarial activity, to the sub-micromolar level, maintaining their potent Plm II inhibitory activity and low cytotoxicity

  纤溶酶（Plm）是新型抗疟药的潜在靶标，但是大多数报道的Plm抑制剂具有相对较低的抗疟活性。我们合成了一系列的二肽型HIV蛋白酶抑制剂，其中含有一个别苯基去甲他汀-二甲基硫代脯氨酸支架，以表现出对Plm II的有效抑制活性。在感染的红细胞分析中，它们对恶性疟原虫的活性与针对靶酶的活性有很大不同。为了提高拟肽Plm抑制剂的抗疟疾活性，我们在高效Plm抑制剂KNI-10006的结构上连接了取代基。在这些衍生物中，我们确定了烷基氨基化合物，例如44（KNI-10283）和47（KNI-10538），其抗疟活性提高了15倍以上，达到亚微摩尔水平，保持其强大的Plm II抑制活性和低细胞毒性。这些结果表明，特定碱性基团上的辅助取代基有助于将抑制剂递送至靶标Plm。
• 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.
• Small-Sized Human Immunodeficiency Virus Type-1 Protease Inhibitors Containing Allophenylnorstatine to Explore the S₂′ Pocket
  作者：Koushi Hidaka、Tooru Kimura、Hamdy M. Abdel-Rahman、Jeffrey-Tri Nguyen、Keith F. McDaniel、William E. Kohlbrenner、Akhteruzzaman Molla、Motoyasu Adachi、Taro Tamada、Ryota Kuroki、Noriko Katsuki、Yoshiaki Tanaka、Hikaru Matsumoto、Jun Wang、Yoshio Hayashi、Dale J. Kempf、Yoshiaki Kiso

  DOI：10.1021/jm9005115

  日期：2009.12.10

  A series of HIV protease inhibitor based on the allophenylnorstatine structure with various P-2' moieties were synthesized. Among these analogues, we discovered that a small allyl group would maintain potent enzyme inhibitory activity compared to the o-methylbenzyl moiety in clinical candidate I (KNI-764, also known as JE-2147, AG-1776, or SM-319777). Introduction of all anilinic amino group to 2 (KNI-727) improved water-solubility and anti-HIV-1 activity, X-ray crystallographic analysis of 13k (KNI-1689) with a beta-methallyl group kit P-2' position revealed hydrophobic interactions with Ala28, Ile84, kind Ile50' similar to that of 1. The presence of an additional methyl group on the allyl group in compound 13k significantly increased anti-HIV activity over 1 while providing a rational drug design for structural minimization and improving membrane permeability.
• How Much Binding Affinity Can be Gained by Filling a Cavity?
  作者：Yuko Kawasaki、Eduardo E. Chufan、Virginie Lafont、Koushi Hidaka、Yoshiaki Kiso、L. Mario Amzel、Ernesto Freire

  DOI：10.1111/j.1747-0285.2009.00921.x

  日期：2010.2

  Binding affinity optimization is critical during drug development. Here, we evaluate the thermodynamic consequences of filling a binding cavity with functionalities of increasing van der Waals radii (–H, –F, –Cl, and CH3) that improve the geometric fit without participating in hydrogen bonding or other specific interactions. We observe a binding affinity increase of two orders of magnitude. There appears to be three phases in the process. The first phase is associated with the formation of stable van der Waals interactions. This phase is characterized by a gain in binding enthalpy and a loss in binding entropy, attributed to a loss of conformational degrees of freedom. For the specific case presented in this article, the enthalpy gain amounts to −1.5 kcal/mol while the entropic losses amount to +0.9 kcal/mol resulting in a net 3.5‐fold affinity gain. The second phase is characterized by simultaneous enthalpic and entropic gains. This phase improves the binding affinity 25‐fold. The third phase represents the collapse of the trend and is triggered by the introduction of chemical functionalities larger than the binding cavity itself [CH(CH3)2]. It is characterized by large enthalpy and affinity losses. The thermodynamic signatures associated with each phase provide guidelines for lead optimization.