6-cyclopentyl-4-hydroxy-6-[2-(4-hydroxyphenyl)ethyl]-5,6-dihydro-pyran-2-one | 260257-56-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 酚类
• 英文名称: 6-cyclopentyl-4-hydroxy-6-[2-(4-hydroxyphenyl)ethyl]-5,6-dihydro-pyran-2-one
• 英文别名: 6-cyclopentyl-6-[2-(4-hydroxyphenyl)ethyl]-4-hydroxy-5,6-dihydropyran-2-one；6-cyclopentyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one；2-cyclopentyl-4-hydroxy-2-[2-(4-hydroxyphenyl)ethyl]-3H-pyran-6-one
• CAS: 260257-56-5
• 化学式: C₁₈H₂₂O₄
• 分子量: 302.37
• InChiKey: HMLRTGISDFGQMN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  66.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester 、 6-cyclopentyl-4-hydroxy-6-[2-(4-hydroxyphenyl)ethyl]-5,6-dihydro-pyran-2-one 在 potassium carbonate 作用下， 以 DMF (N,N-dimethyl-formamide) 为溶剂， 以63%的产率得到3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-cyclopentyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one
  参考文献：
  名称：

  [EN] INHIBITORS OF HEPATITIS C VIRUS RNA-DEPENDENT RNA POLYMERASE, AND COMPOSITIONS AND TREATMENTS USING THE SAME
  [FR] INHIBITEURS DE L'ARN POLYMERASE ARN-DEPENDANTE DU VIRUS DE L'HEPATITE C ET COMPOSITIONS ET TRAITEMENTS UTILISANT CETTE POLYMERASE

  摘要：

  化合物的化学式（I）是丙型肝炎病毒（HCV）RNA依赖性RNA聚合酶（RdRp）抑制剂，对感染丙型肝炎病毒的人进行治疗和预防性治疗具有用处。

  公开号：

  WO2003095441A1
• 作为产物：
  描述：

  3-[4-(苄氧基)苯基]丙酸 在 palladium on activated charcoal 吡啶 、 正丁基锂 、 氯化亚砜 、 氢气 、 sodium hydride 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 二氯甲烷 为溶剂， 20.0 ℃ 、344.74 kPa 条件下， 反应 39.0h， 生成 6-cyclopentyl-4-hydroxy-6-[2-(4-hydroxyphenyl)ethyl]-5,6-dihydro-pyran-2-one
  参考文献：
  名称：

  Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390: a lead HIV protease inhibitor

  摘要：

  With the insight generated by the availability of X-ray crystal structures of various 5,6-dihydropyran-2-ones bound to HIV PR, inhibitors possessing various alkyl groups at the 6-position of 5,6-dihydropyran-2-one ring were synthesized. The inhibitors possessing a 6-alkyl group exhibited superior antiviral activities when compared to 6-phenyl analogues. Antiviral efficacies were further improved upon introduction of a polar group (hydroxyl or amino) on the 4-position of the phenethyl moiety as well as the polar group (hydroxymethyl) on the 3-(tert-butyl-5-methyl-phenylthio) moiety. The polar substitution is also advantageous for decreasing toxicity, providing inhibitors with higher therapeutic indices. The best inhibitor among this series, (S)-6-[2-(4-aminophenyl)-ethyl]-(3-(2-tert-butyl-5-methyl-phenylsulfa nyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one (34S), exhibited an EC50 of 200 nM with a therapeutic index of > 1000. More importantly, these non-peptidic inhibitors, 16S and 34S, appear to offer little cross-resistance to the currently marketed peptidomimetic PR inhibitors. The selected inhibitors tested in vitro against mutant HIV PR showed a very small increase in binding affinities relative to wild-type HIV PR. Cmax and absolute bioavailability of 34S were higher and half-life and time above EC95 were longer compared to 16S. Thus 34S, also known as PD 178390, which displays good antiviral efficacy, promising pharmacokinetic characteristics and favorable activity against mutant enzymes and CYP3A4, has been chosen for further preclinical evaluation.

  DOI：

  10.1016/s0968-0896(99)00215-1

文献信息

• Hepatitis C virus (HCV) NS5B RNA polymerase and mutants thereof
  申请人：Agouron Pharmaceuticals, Inc.

  公开号：EP1256628A9

  公开（公告）日：2003-04-16

  The present invention generally relates to viral RNA polymerases, which are essential to viral reproduction and propagation in a host. Viral RNA polymerases are known to play a role in the replication of the virus once it has infected its host. The present invention relates to mutants of native Hepatitis C Virus (HCV) RNA polymerase, said mutants imparting improved crystallization properties of the enzyme and enzyme/compound complexes. The present invention also relates to the isolation and identification of an allosteric binding cleft within the HCV NS5B RNA polymerase and its use in the discovery, identification, and characterization of inhibitors of same.

  本发明通常涉及病毒RNA聚合酶，该酶对于病毒在宿主体内的复制和传播至关重要。已知病毒RNA聚合酶在病毒感染宿主后的复制中发挥作用。本发明涉及天然丙型肝炎病毒（HCV）RNA聚合酶的突变体，该突变体赋予酶和酶/化合物复合物改进的结晶性能。本发明还涉及在HCV NS5B RNA聚合酶中分离和鉴定一个变构结合裂隙及其在发现、鉴定和表征其抑制剂方面的应用。
• Hepatitis c virus (hcv) ns5b rna polymerase and mutants thereof
  申请人：Agouron Pharmaceuticals, Inc.

  公开号：EP1256628A2

  公开（公告）日：2002-11-13

  The present invention generally relates to viral RNA polymerases, which are essential to viral reproduction and propagation in a host. Viral RNA polymerases are known to play a role in the replication of the virus once it has infected its host. The present invention relates to mutants of native Hepatitis C Virus (HCV) RNA polymerase, said mutants imparting improved crystallization properties of the enzyme and enzyme/compound complexes. The present invention also relates to the isolation and identification of an allosteric binding cleft within the HCV NS5B RNA polymerase and its use in the discovery, identification, and characterization of inhibitors of same.

  本发明一般涉及病毒 RNA 聚合酶，它对病毒在宿主体内的繁殖和传播至关重要。 已知病毒 RNA 聚合酶在病毒感染宿主后的复制过程中发挥作用。 本发明涉及原生丙型肝炎病毒（HCV）RNA 聚合酶的突变体，所述突变体可改善酶和酶/化合物复合物的结晶特性。 本发明还涉及分离和鉴定 HCV NS5B RNA 聚合酶内的异生结合裂隙，并将其用于发现、鉴定和表征其抑制剂。
• Inhibitors of hepatitis C virus RNA-dependent RNA polymerase, and compositions and treatments using the same
  申请人：Agouron Pharmaceuticals, Inc.

  公开号：US20040023958A1

  公开（公告）日：2004-02-05

  Compounds of formula I are hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) inhibitors, and are useful in therapeutic and prophylactic treatment of persons infected with hepatitis C virus. 1

  式 I 的化合物是丙型肝炎病毒（HCV）RNA 依赖性 RNA 聚合酶（RdRp）抑制剂，可用于丙型肝炎病毒感染者的治疗和预防。 1
• 5,6-Dihydropyran-2-ones Possessing Various Sulfonyl Functionalities:  Potent Nonpeptidic Inhibitors of HIV Protease
  作者：Frederick E. Boyer、J. V. N. Vara Prasad、John M. Domagala、Edmund L. Ellsworth、Christopher Gajda、Susan E. Hagen、Larry J. Markoski、Bradley D. Tait、Elizabeth A. Lunney、Alexander Palovsky、Donna Ferguson、Neil Graham、Tod Holler、Donald Hupe、Carolyn Nouhan、Peter J. Tummino、A. Urumov、Eric Zeikus、Greg Zeikus、Stephen J. Gracheck、James M. Sanders、Steven VanderRoest、Joanne Brodfuehrer、Krishna Iyer、Michael Sinz、Sergei V. Gulnik、John W. Erickson

  DOI：10.1021/jm990281p

  日期：2000.3.1

  On the basis of previous SAR findings and molecular modeling studies, a series of compounds were synthesized which possessed various sulfonyl moieties substituted at the 4-position of the C-3 phenyl ring substituent of the dihydropyran-2-one ring system. The sulfonyl substituents were added in an attempt to fill the additional S-3' pocket and thereby produce increasingly potent inhibitors of the target enzyme. Racemic and enantiomerically resolved varieties of selected compounds were synthesized. All analogues in the study displayed decent binding affinity to HIV protease, and several compounds were shown to possess very good antiviral efficacy and safety margins. X-ray crystallographic structures confirmed that the sulfonamide and sulfonate moieties were filling the S3' pocket of the enzyme. However, the additional substituent did not provide improved enzymatic inhibitory or antiviral activity as compared to the resolved unsubstituted aniline. The addition of the sulfonyl moiety substitution does not appear to provide favorable pharamacokinectic parameters. Selected inhibitors were tested for antiviral activity in clinical isolates and exhibited similar antiviral activity against all of the HIV-1 strains tested as they did against the wild-type HIV-1, In addition, the inhibitors exhibited good antiviral efficacies against HIV-1 strains that displayed resistance to the currently marketed protease inhibitors.
• Nonpeptidic HIV protease inhibitors: 6-alkyl-5, 6-dihydropyran-2-ones possessing achiral 3-(4-amino/carboxamide-2-t-butyl, 5-methylphenyl thio) moiety: Antiviral activities and pharmacokinetic properties
  作者：J.V.N. Vara Prasad、Fred E. Boyer、John M. Domagala、Edmund L. Ellsworth、Christopher Gajda、Susan E. Hagen、Larry J. Markoski、Bradley D. Tait、Elizabeth A. Lunney、Peter J. Tummino、Donna Ferguson、Tod Holler、Donald Hupe、Carolyn Nouhan、Stephen J. Gracheck、Steven VanderRoest、James Saunders、Krishna Iyer、Michael Sinz、Joanne Brodfuehrer

  DOI：10.1016/s0960-894x(99)00237-1

  日期：1999.6

  Dihydropyran-2-ones possessing amino and carboxamide functionalities on 3-SPh (2-tert-butyl, 5-methyl) ring were synthesized and evaluated for their antiviral activities. Both the enantiomers of inhibitor 15 were synthesized. The in vitro resistance profile, inhibitory activities against cytochrome P450 isozymes and pharmacokinetic properties of inhibitor 15S will be discussed.