Carbonic acid 4-nitro-phenyl ester oxazol-5-ylmethyl ester | 165315-68-4

• 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: Carbonic acid 4-nitro-phenyl ester oxazol-5-ylmethyl ester
• 英文别名: (4-Nitrophenyl) 1,3-oxazol-5-ylmethyl carbonate
• CAS: 165315-68-4
• 化学式: C₁₁H₈N₂O₆
• 分子量: 264.194
• InChiKey: KMCBAXNMMZXNIZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  19
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  107
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (S)-N-((2R,5R)-5-amino-1,6-diphenylhexan-2-yl)-2-(3-((2-isopropylthiazol-4-yl)methyl)-3-methylureido)-3-methylbutanamide hydrochloride 、 Carbonic acid 4-nitro-phenyl ester oxazol-5-ylmethyl ester 在 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 16.0h， 生成 oxazol-5-ylmethyl [(2R,5R)-5-((S)-2-(3-((2-isopropylthiazol-4-yl)methyl)-3-methylureido)-3-methylbutanamido)-1,6-diphenylhexan-2-yl]carbamate
  参考文献：
  名称：

  Pyridine-Substituted Desoxyritonavir Is a More Potent Inhibitor of Cytochrome P450 3A4 than Ritonavir

  摘要：

  Utilization of the cytochrome P450 3A4 (CYP3A4) inhibitor ritonavir as a pharmacoenhancer for anti-HIV drugs revolutionized the treatment of HIV infection. However, owing to ritonavir-related complications, there is a need for development of new CYP3A4 inhibitors with improved pharmacochemical properties, which requires a full understanding of the CYP3A4 inactivation mechanisms and the unraveling of possible inhibitor binding modes. We investigated the mechanism of CYP3A4 interaction with three desoxyritonavir analogues, containing the heme-ligating imidazole, oxazole, or pyridine group instead of the thiazole moiety (compounds 1, 2, and 3, respectively). Our data show that compound 3 is superior to ritonavir in terms of binding affinity and inhibitory potency owing to greater flexibility and the ability to adopt a conformation that minimizes steric clashing and optimizes protein-ligand interactions. Additionally, Ser119 was identified as a key residue assisting binding of ritonavir-like inhibitors, which emphasizes the importance of polar interactions in the CYP3A4-ligand association.

  DOI：

  10.1021/jm400288z
• 作为产物：
  描述：

  二(对硝基苯)碳酸酯 、 噁唑-5-甲醇 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 16.0h， 生成 Carbonic acid 4-nitro-phenyl ester oxazol-5-ylmethyl ester
  参考文献：
  名称：

  Pyridine-Substituted Desoxyritonavir Is a More Potent Inhibitor of Cytochrome P450 3A4 than Ritonavir

  摘要：

  Utilization of the cytochrome P450 3A4 (CYP3A4) inhibitor ritonavir as a pharmacoenhancer for anti-HIV drugs revolutionized the treatment of HIV infection. However, owing to ritonavir-related complications, there is a need for development of new CYP3A4 inhibitors with improved pharmacochemical properties, which requires a full understanding of the CYP3A4 inactivation mechanisms and the unraveling of possible inhibitor binding modes. We investigated the mechanism of CYP3A4 interaction with three desoxyritonavir analogues, containing the heme-ligating imidazole, oxazole, or pyridine group instead of the thiazole moiety (compounds 1, 2, and 3, respectively). Our data show that compound 3 is superior to ritonavir in terms of binding affinity and inhibitory potency owing to greater flexibility and the ability to adopt a conformation that minimizes steric clashing and optimizes protein-ligand interactions. Additionally, Ser119 was identified as a key residue assisting binding of ritonavir-like inhibitors, which emphasizes the importance of polar interactions in the CYP3A4-ligand association.

  DOI：

  10.1021/jm400288z

文献信息

• [EN] RETROVIRAL PROTEASE INHIBITING COMPOUNDS<br/>[FR] COMPOSES INHIBANT DES PROTEASES RETROVIRALES
  申请人：ABBOTT LABORATORIES

  公开号：WO1994014436A1

  公开（公告）日：1994-07-07

  (EN) A retroviral protease inhibiting compound of formula (A) is disclosed.(FR) L'invention se rapporte à un composé inhibant des protéases rétrovirales, qui est présenté par la formule (A).

  一种抑制反转录病毒蛋白酶的化合物公式（A）已被披露。(法语)本发明涉及一种通过公式（A）表示的抑制反转录病毒蛋白酶的化合物。
• Processes and intermediates for manufacturing retroviral protease inhibiting compounds
  申请人：ABBOTT LABORATORIES

  公开号：EP1090914A2

  公开（公告）日：2001-04-11

  A retroviral protease inhibiting compound of formula (A) is disclosed for use in combination with other active pharmaceutical agents for treating a human infected by HIV. Intermediates and processes useful in the manufacture of compounds of formula (A) are also disclosed.

  本发明公开了一种抑制逆转录病毒蛋白酶的式(A)化合物，该化合物可与其他活性药剂联合使用，用于治疗受艾滋病毒感染的人。还公开了用于制造式（A）化合物的中间体和工艺。
• WO2008/11117
  申请人：——

  公开号：——

  公开（公告）日：——
• Discovery of Ritonavir, a Potent Inhibitor of HIV Protease with High Oral Bioavailability and Clinical Efficacy
  作者：Dale J. Kempf、Hing L. Sham、Kennan C. Marsh、Charles A. Flentge、David Betebenner、Brian E. Green、Edith McDonald、Sudthida Vasavanonda、Ayda Saldivar、Norman E. Wideburg、Warren M. Kati、Lisa Ruiz、Chen Zhao、LynnMarie Fino、Jean Patterson、Akhteruzzaman Molla、Jacob J. Plattner、Daniel W. Norbeck

  DOI：10.1021/jm970636+

  日期：1998.2.1

  The structure-activity studies leading to the potent and clinically efficacious HIV protease inhibitor ritonavir are described. Beginning with the moderately potent and orally bioavailable inhibitor A-80987, systematic investigation of peripheral (P3 and P2') heterocyclic groups designed to decrease the rate of hepatic metabolism provided analogues with improved pharmacokinetic properties after oral dosing in rats. Replacement of pyridyl groups with thiazoles provided increased chemical stability toward oxidation while maintaining sufficient aqueous solubility for oral absorption, Optimization of hydrophobic interactions with the HIV protease active site produced ritonavir, with excellent in vitro potency (EC50 = 0.02 mu M) and high and sustained plasma concentrations after oral administration in four species. Details of the discovery and preclinical development of ritonavir are described.
• RETROVIRAL PROTEASE INHIBITING COMPOUNDS
  申请人：ABBOTT LABORATORIES

  公开号：EP0674513B1

  公开（公告）日：1996-09-25