(8aS)-7-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-pyrrol-3-yl]-1,2,3,5,6,8a-hexahydroindolizine | 321344-57-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: (8aS)-7-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-pyrrol-3-yl]-1,2,3,5,6,8a-hexahydroindolizine
• 英文别名: R-132811；(S)-2-(4-fluorophenyl)-4-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-3-(pyridin-4-yl)-1H-pyrrole；(-)-2-(4-fluorophenyl)-4-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-3-(pyridin-4-yl)-1H-pyrrole；4V9C6Fbz7M
• CAS: 321344-57-4
• 化学式: C₂₃H₂₂FN₃
• 分子量: 359.446
• InChiKey: KVBWUPVGVUIAIX-FQEVSTJZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  31.9
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  在 四丁基氟化铵 作用下， 以 四氢呋喃 为溶剂， 生成 (8aS)-7-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-pyrrol-3-yl]-1,2,3,5,6,8a-hexahydroindolizine
  参考文献：
  名称：

  Tetrahydropyridine derivatives with inhibitory activity on the production of proinflammatory cytokines: Part 3

  摘要：

  In order to develop a new class of anti-rheumatic drug which inhibits production of proinflammatory cytokines such as TNF alpha, IL-1 beta, IL-6, and IL-8, a series of 3-pyridylpyrrole derivatives possessing a bicyclic tetrahydropyridine moiety at the 4-position of the pyrrole ring were synthesized and their pharmacological activities were evaluated. The derivatives were found to have potent inhibitory activities on the production of the cytokines both in vitro and in vivo. Among them, compound 4a, (S)-2-(4-fluorophenyl)-4-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-3-(pyridin-4-yl)-1H-pyrrole (R-132811), achieved the most promising results in various in vitro and in vivo tests including several rheumatoid arthritis models ((i) inhibition of p38 alpha, p38 beta, p38 gamma, and p38 delta MAP kinases: IC50 = 0.034, 0.572, >10, and >10 mu M, respectively; (ii) inhibition of TNF alpha, IL-1 beta, IL-6, and IL-8 production in human whole blood: IC50 = 0.026, 0.020, 0.88, and 0.016 mu M, respectively; (iii) inhibition of LPS induced TNF alpha, IL-1 beta and IL-6 production in mice: ID50 = 0.93, 8.63, and 0.11 mg/kg, po, respectively; (iv) inhibition of anti-collagen antibody-induced arthritis in mice: ID50 = 2.22 mg/kg, po; (v) inhibition of collagen-induced arthritis in mice: ID50 = 2.38 mg/kg, po; (vi) prophylactic effect on adjuvant-induced arthritis in rats: ID50 = 3.1 mg/kg, po; (vii) therapeutic effect on adjuvant-induced arthritis in rats: ID50 = 4.9 mg/kg, po; (viii) analgesic effect on adjuvant-induced arthritic pain in rats: ID50 = 2.9 mg/kg, po). As a result, compound 4a was chosen as a candidate for further pre-clinical studies. Crown Copyright (C) 2010 Published by Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.06.122

文献信息

• Heteroaryl-substituted pyrrole derivates, their preparation and their therapeutic uses
  申请人：Sankyo Company Limited

  公开号：EP1243589A1

  公开（公告）日：2002-09-25

  Compounds of formula (I): [wherein: A is a pyrrole ring; R1 is an optionally substituted phenyl or naphthyl group; R2 is an optionally substituted pyridyl or pyrimidinyl group; R3 represents a group of the formula -X-R4, wherein X is a single bond or an alkenylene group, and R4 is an optionally substituted nitrogen-containing heterocyclyl group; selected from the group consisting of 8-azabicyclo[3.2.1]octenyl, 9-azabicyclo[3.3.1]nonenyl and quinuclidinenyl groups, PROVIDED THAT said substituents R1 and R3 are bonded to the two atoms of said pyrrole ring which are adjacent to the atom of the pyrrole ring to which said substituent R2 is bonded] have excellent inhibitory activity against the production of inflammatory cytokines.

  化合物的结构式（I）：[其中：A为吡咯环；R1为可选取代的苯或萘基团；R2为可选取代的吡啶或嘧啶基团；R3代表具有下述结构的基团-X-R4，其中X为单键或烯基链，R4为可选取代的含氮杂环基团；所选取自8-氮杂双环[3.2.1]辛烯基、9-氮杂双环[3.3.1]壬烯基和喹啉环基团，前提是所述取代基R1和R3连接到所述吡咯环的两个相邻原子，这两个原子与所述取代基R2连接的吡咯环原子相邻]具有出色的抑制炎症细胞因子产生活性。
• Tetrahydropyridine derivatives with inhibitory activity on the production of proinflammatory cytokines: Part 3
  作者：Akira Nakao、Nobuyuki Ohkawa、Takayoshi Nagasaki、Takashi Kagari、Hiromi Doi、Takaichi Shimozato、Shigeru Ushiyama、Kazumasa Aoki

  DOI：10.1016/j.bmcl.2010.06.122

  日期：2010.8

  In order to develop a new class of anti-rheumatic drug which inhibits production of proinflammatory cytokines such as TNF alpha, IL-1 beta, IL-6, and IL-8, a series of 3-pyridylpyrrole derivatives possessing a bicyclic tetrahydropyridine moiety at the 4-position of the pyrrole ring were synthesized and their pharmacological activities were evaluated. The derivatives were found to have potent inhibitory activities on the production of the cytokines both in vitro and in vivo. Among them, compound 4a, (S)-2-(4-fluorophenyl)-4-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-3-(pyridin-4-yl)-1H-pyrrole (R-132811), achieved the most promising results in various in vitro and in vivo tests including several rheumatoid arthritis models ((i) inhibition of p38 alpha, p38 beta, p38 gamma, and p38 delta MAP kinases: IC50 = 0.034, 0.572, >10, and >10 mu M, respectively; (ii) inhibition of TNF alpha, IL-1 beta, IL-6, and IL-8 production in human whole blood: IC50 = 0.026, 0.020, 0.88, and 0.016 mu M, respectively; (iii) inhibition of LPS induced TNF alpha, IL-1 beta and IL-6 production in mice: ID50 = 0.93, 8.63, and 0.11 mg/kg, po, respectively; (iv) inhibition of anti-collagen antibody-induced arthritis in mice: ID50 = 2.22 mg/kg, po; (v) inhibition of collagen-induced arthritis in mice: ID50 = 2.38 mg/kg, po; (vi) prophylactic effect on adjuvant-induced arthritis in rats: ID50 = 3.1 mg/kg, po; (vii) therapeutic effect on adjuvant-induced arthritis in rats: ID50 = 4.9 mg/kg, po; (viii) analgesic effect on adjuvant-induced arthritic pain in rats: ID50 = 2.9 mg/kg, po). As a result, compound 4a was chosen as a candidate for further pre-clinical studies. Crown Copyright (C) 2010 Published by Elsevier Ltd. All rights reserved.