1-(4-Bromo-benzyl)-5-methanesulfonyl-1H-indole-2-carboxylic acid methyl ester | 416901-59-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 1-(4-Bromo-benzyl)-5-methanesulfonyl-1H-indole-2-carboxylic acid methyl ester
• 英文别名: methyl 1-[(4-bromophenyl)methyl]-5-methylsulfonylindole-2-carboxylate
• CAS: 416901-59-2
• 化学式: C₁₈H₁₆BrNO₄S
• 分子量: 422.299
• InChiKey: OOWZNIPZLXBTAA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  73.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  对溴溴苄 、 甲基 5-甲基磺基吲哚-2-甲酯 在 氢氧化钾 作用下， 以 甲醇 、 丙酮 为溶剂， 以95%的产率得到1-(4-Bromo-benzyl)-5-methanesulfonyl-1H-indole-2-carboxylic acid methyl ester
  参考文献：
  名称：

  Identification of Novel Cyclooxygenase-2 Selective Inhibitors Using Pharmacophore Models

  摘要：

  In the present study we have investigated whether pharmacophore models may account for the activity and selectivity of the known cyclooxygenase-2 (COX-2) selective inhibitors of the phenylsulfonyl tricyclic series, i.e., Celecoxib (1) and Rofecoxib (3), and whether transferring this structural information onto the frame of a nonsteroidal anti inflammatory drug (NSAID), known to tightly bind the enzyme active site, may be useful for designing novel COX-2 selective inhibitors. With this aim we have developed a pharmacophore based on the geometric disposition of chemical features in the most favorable conformation of the COX-2 selective inhibitors SC-558 (2; analogue of Celecoxib (1)) and Rofecoxib (3) and the more restrained compounds 4 (DFU) and 5. The pharmacophore model contains a sulfonyl S atom, an aromatic ring (ring plane A) with a fixed position of the normal to the plane, and an additional aromatic ring (ring plane B), both rings forming a dihedral angle of 290degrees +/- 10degrees. The final disposition of the pharmacophoric groups parallels the geometry of the ligand SC-558 (2) in the known crystal structure of the COX-2 complex. Moreover, the nonconserved residue 523 is known to be important for COX-2 selective inhibition; thus, the crystallographic information was used to position an excluded volume in the pharmacophore, accounting for the space limits imposed by this nonconserved residue. The geometry of the final five-feature pharmacophore was found to be consistent with the crystal structure of the nonselective NSAID indomethacin (6) in the COX-2 complex. This result was used to design indomethacin analogues 8 and 9 that exhibited consistent structure-activity relationships leading to the potent and selective COX-2 inhibitor Sa. Compound 8a (LM-1685) was selected as a promising candidate for further pharmacological evaluation.

  DOI：

  10.1021/jm010458r

文献信息

• Identification of Novel Cyclooxygenase-2 Selective Inhibitors Using Pharmacophore Models
  作者：Albert Palomer、Francesc Cabré、Jaume Pascual、Joaquín Campos、María A. Trujillo、Antonio Entrena、Miguel A. Gallo、Lluïsa García、David Mauleón、Antonio Espinosa

  DOI：10.1021/jm010458r

  日期：2002.3.1

  In the present study we have investigated whether pharmacophore models may account for the activity and selectivity of the known cyclooxygenase-2 (COX-2) selective inhibitors of the phenylsulfonyl tricyclic series, i.e., Celecoxib (1) and Rofecoxib (3), and whether transferring this structural information onto the frame of a nonsteroidal anti inflammatory drug (NSAID), known to tightly bind the enzyme active site, may be useful for designing novel COX-2 selective inhibitors. With this aim we have developed a pharmacophore based on the geometric disposition of chemical features in the most favorable conformation of the COX-2 selective inhibitors SC-558 (2; analogue of Celecoxib (1)) and Rofecoxib (3) and the more restrained compounds 4 (DFU) and 5. The pharmacophore model contains a sulfonyl S atom, an aromatic ring (ring plane A) with a fixed position of the normal to the plane, and an additional aromatic ring (ring plane B), both rings forming a dihedral angle of 290degrees +/- 10degrees. The final disposition of the pharmacophoric groups parallels the geometry of the ligand SC-558 (2) in the known crystal structure of the COX-2 complex. Moreover, the nonconserved residue 523 is known to be important for COX-2 selective inhibition; thus, the crystallographic information was used to position an excluded volume in the pharmacophore, accounting for the space limits imposed by this nonconserved residue. The geometry of the final five-feature pharmacophore was found to be consistent with the crystal structure of the nonselective NSAID indomethacin (6) in the COX-2 complex. This result was used to design indomethacin analogues 8 and 9 that exhibited consistent structure-activity relationships leading to the potent and selective COX-2 inhibitor Sa. Compound 8a (LM-1685) was selected as a promising candidate for further pharmacological evaluation.