(+)-1-(3-chlorobenzyl)-4-methyl-6-<(5-phenylpyridin-2-yl)methoxy>-4,5-dihydro-1H-thiopyrano<2,3,4-c,d>indole-2-methanol

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: (+)-1-(3-chlorobenzyl)-4-methyl-6-<(5-phenylpyridin-2-yl)methoxy>-4,5-dihydro-1H-thiopyrano<2,3,4-c,d>indole-2-methanol
• 英文别名: [2-[(3-Chlorophenyl)methyl]-6-methyl-9-[(5-phenylpyridin-2-yl)methoxy]-5-thia-2-azatricyclo[6.3.1.04,12]dodeca-1(12),3,8,10-tetraen-3-yl]methanol
• 化学式: C₃₁H₂₇ClN₂O₂S
• 分子量: 527.087
• InChiKey: MMYYQNOUWXIQRZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  37
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  72.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (+)-1-(3-chlorobenzyl)-4-methyl-6-<(5-phenylpyridin-2-yl)methoxy>-4,5-dihydro-1H-thiopyrano<2,3,4-c,d>indole-2-methanol 在 lithium hydroxide 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 2.0h， 生成 2-<<1-(3-chlorobenzyl)-4-methyl-6-<(5-phenylpyridin-2-yl)methoxy>-4,5-dihydro-1H-thiopyrano<2,3,4-c,d>indol-2-yl>methoxy>phenylacetic acid
  参考文献：
  名称：

  Thiopyranol[2,3,4-c,d]indoles as Inhibitors of 5-Lipoxygenase, 5-Lipoxygenase-Activating Protein, and Leukotriene C4 Synthase

  摘要：

  The attachment of an arylacetic or benzoic acid moiety to the thiopyrano[2,3,4-c,d]indole nucleus results in compounds which are highly potent and selective 5-lipoxygenase (5-LO) inhibitors. These compounds are structurally simpler than previous compounds of similar potency in that they contain a single chiral center. From the data presented, 2-[[1-(3-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy]-4,5-dihydro-1H-thiopyrano [2,3,4-c,d]indol-2-yl]methoxy]phenylacetic acid, 14b, was shown to inhibit 5-hydroperoxyeicosatetraenoic acid (5-HPETE) production by human 5-LO (IC50 of 18 nM). The acid 14b is highly selective as an inhibitor of 5-LO activity when compared to the inhibition of ram seminal vesicle cyclooxygenase (IC50 > 5 mu M) or human leukocyte leukotriene A(4) (LTA(4)) hydrolase (IC50 > 20 mu M). In addition, 14b was inactive in a 5-lipoxygenase-activating protein (FLAP) binding assay at 10 mu M. In vivo studies showed that 14b is bioavailable in rat and functionally active in the hyperreactive rat model of antigen-induced dyspnea (74% inhibition at 0.5 mg/kg po; 2 h pretreatment). In the conscious squirrel monkey model of asthma, 14b showed excellent functional activity at 0.1 mg/kg against antigen-induced bronchoconstriction (94% inhibition of the increase in R(L) and 100% inhibition in the decrease in C-dyn; n = 4) Resolution of this compound gave (-)-14b, the most potent enantiomer (IC50 = 10 nM in the human 5-LO assay), which was shown to possess the S configuration at the chiral center by X-ray crystallographic analysis of an intermediate. Subsequent studies on the aryl thiopyrano[2,3,4-c,d]indole series of inhibitors led to the discovery of potent dual inhibitors of both FLAP and 5-LO, the most potent of which is 2-[[1-(4-chlorobenzyl)-4-methyl-6-(quinolin-2-ylmethoxy) -4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]methoxy]phenylacetic acid, 19. Acid 19 has an IC50 of 100 nM for the inhibition of 5-HPETE production by human 5-LO and is active in a FLAP binding assay with an IC50 of 32 nM. Furthermore, thiopyrano[2,3,4-c,d]indoles such as 1 and 14b are capable of inhibiting the LTC(4) synthase reaction in a dose dependent manner (IC(50)s of 11 and 16 mu M, respectively, compared to that of LTC(2) at 1.2 mu M) in contrast to other, structurally distinct 5-LO inhibitors. It has also been observed that the thiopyrano[2,3,4-c,d]indole class of compounds strongly promotes the translocation of 5-LO from the cytosol to a membrane fraction in the presence or absence of the ionophore A23187. The membrane-bound 5-LO retains its activity, and this association with the membrane is not reversed with the FLAP inhibitor MK-886. These observations, in part, support the hypothesis that these compounds act by binding at the arachidonic acid-binding site on FLAP, 5-LO, and LTC(4) synthase and that the thiopyrano[2,3,4-c,d]indole is capable of mimicking an active conformation of arachidonic acid.

  DOI：

  10.1021/jm00022a020
• 作为产物：
  描述：

  2-(氯甲基)-5-苯基吡啶 、 2-[(3-chlorophenyl)methyl]-3-(hydroxymethyl)-6-methyl-5-thia-2-azatricyclo[6.3.1.04,12]dodeca-1(12),3,8,10-tetraen-9-ol 在 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 16.0h， 生成 (+)-1-(3-chlorobenzyl)-4-methyl-6-<(5-phenylpyridin-2-yl)methoxy>-4,5-dihydro-1H-thiopyrano<2,3,4-c,d>indole-2-methanol
  参考文献：
  名称：

  Thiopyranol[2,3,4-c,d]indoles as Inhibitors of 5-Lipoxygenase, 5-Lipoxygenase-Activating Protein, and Leukotriene C4 Synthase

  摘要：

  The attachment of an arylacetic or benzoic acid moiety to the thiopyrano[2,3,4-c,d]indole nucleus results in compounds which are highly potent and selective 5-lipoxygenase (5-LO) inhibitors. These compounds are structurally simpler than previous compounds of similar potency in that they contain a single chiral center. From the data presented, 2-[[1-(3-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy]-4,5-dihydro-1H-thiopyrano [2,3,4-c,d]indol-2-yl]methoxy]phenylacetic acid, 14b, was shown to inhibit 5-hydroperoxyeicosatetraenoic acid (5-HPETE) production by human 5-LO (IC50 of 18 nM). The acid 14b is highly selective as an inhibitor of 5-LO activity when compared to the inhibition of ram seminal vesicle cyclooxygenase (IC50 > 5 mu M) or human leukocyte leukotriene A(4) (LTA(4)) hydrolase (IC50 > 20 mu M). In addition, 14b was inactive in a 5-lipoxygenase-activating protein (FLAP) binding assay at 10 mu M. In vivo studies showed that 14b is bioavailable in rat and functionally active in the hyperreactive rat model of antigen-induced dyspnea (74% inhibition at 0.5 mg/kg po; 2 h pretreatment). In the conscious squirrel monkey model of asthma, 14b showed excellent functional activity at 0.1 mg/kg against antigen-induced bronchoconstriction (94% inhibition of the increase in R(L) and 100% inhibition in the decrease in C-dyn; n = 4) Resolution of this compound gave (-)-14b, the most potent enantiomer (IC50 = 10 nM in the human 5-LO assay), which was shown to possess the S configuration at the chiral center by X-ray crystallographic analysis of an intermediate. Subsequent studies on the aryl thiopyrano[2,3,4-c,d]indole series of inhibitors led to the discovery of potent dual inhibitors of both FLAP and 5-LO, the most potent of which is 2-[[1-(4-chlorobenzyl)-4-methyl-6-(quinolin-2-ylmethoxy) -4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]methoxy]phenylacetic acid, 19. Acid 19 has an IC50 of 100 nM for the inhibition of 5-HPETE production by human 5-LO and is active in a FLAP binding assay with an IC50 of 32 nM. Furthermore, thiopyrano[2,3,4-c,d]indoles such as 1 and 14b are capable of inhibiting the LTC(4) synthase reaction in a dose dependent manner (IC(50)s of 11 and 16 mu M, respectively, compared to that of LTC(2) at 1.2 mu M) in contrast to other, structurally distinct 5-LO inhibitors. It has also been observed that the thiopyrano[2,3,4-c,d]indole class of compounds strongly promotes the translocation of 5-LO from the cytosol to a membrane fraction in the presence or absence of the ionophore A23187. The membrane-bound 5-LO retains its activity, and this association with the membrane is not reversed with the FLAP inhibitor MK-886. These observations, in part, support the hypothesis that these compounds act by binding at the arachidonic acid-binding site on FLAP, 5-LO, and LTC(4) synthase and that the thiopyrano[2,3,4-c,d]indole is capable of mimicking an active conformation of arachidonic acid.

  DOI：

  10.1021/jm00022a020

文献信息

• US5314900A
  申请人：——

  公开号：US5314900A

  公开（公告）日：1994-05-24
• [EN] ARYL THIOPYRANO[2,3,4-c,d]INDOLES AS INHIBITORS OF LEUKOTRIENE BIOSYNTHESIS<br/>[FR] ARYLTHIOPYRANO[2,3,4-c,d]INDOLES UTILES EN TANT QU'INHIBITEURS DE LA BIOSYNTHESE DE LEUCOTRIENES
  申请人：MERCK FROSST CANADA INC.

  公开号：WO1994011378A1

  公开（公告）日：1994-05-26

  (EN) Compounds having formula (I) are inhibitors of 5-lipoxygenase and inhibitors of leukotriene biosynthesis. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, psoriasis, uveitis, and allograft rejection and in preventing the formation of atherosclerotic plaques.(FR) Les composés de formule (I) sont des inhibiteurs de la 5-lipoxygénase et des inhibiteurs de la biosynthèse de leucotriènes. Ces composés sont utiles en tant qu'agents anti-asthmatiques, anti-allergiques, anti-inflammatoires, et cytoprotecteurs. Ils sont aussi utiles dans le traitement de l'angine, du spasme cérébral, de la néphrite glomérulaire, de l'hépatite, de l'endotoxémie, du psoriasis, de l'uvéite et du rejet de greffe allogénique, et dans la prévention de la formation de plaques d'athérosclérose.
• Thiopyranol[2,3,4-c,d]indoles as Inhibitors of 5-Lipoxygenase, 5-Lipoxygenase-Activating Protein, and Leukotriene C4 Synthase
  作者：John H. Hutchinson、Stella Charleson、Jilly F. Evans、Jean-Pierre Falgueyret、Karst Hoogsteen、Tom R. Jones、Stacia Kargman、Dwight Macdonald、Cyril S. McFarlane

  DOI：10.1021/jm00022a020

  日期：1995.10

  The attachment of an arylacetic or benzoic acid moiety to the thiopyrano[2,3,4-c,d]indole nucleus results in compounds which are highly potent and selective 5-lipoxygenase (5-LO) inhibitors. These compounds are structurally simpler than previous compounds of similar potency in that they contain a single chiral center. From the data presented, 2-[[1-(3-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy]-4,5-dihydro-1H-thiopyrano [2,3,4-c,d]indol-2-yl]methoxy]phenylacetic acid, 14b, was shown to inhibit 5-hydroperoxyeicosatetraenoic acid (5-HPETE) production by human 5-LO (IC50 of 18 nM). The acid 14b is highly selective as an inhibitor of 5-LO activity when compared to the inhibition of ram seminal vesicle cyclooxygenase (IC50 > 5 mu M) or human leukocyte leukotriene A(4) (LTA(4)) hydrolase (IC50 > 20 mu M). In addition, 14b was inactive in a 5-lipoxygenase-activating protein (FLAP) binding assay at 10 mu M. In vivo studies showed that 14b is bioavailable in rat and functionally active in the hyperreactive rat model of antigen-induced dyspnea (74% inhibition at 0.5 mg/kg po; 2 h pretreatment). In the conscious squirrel monkey model of asthma, 14b showed excellent functional activity at 0.1 mg/kg against antigen-induced bronchoconstriction (94% inhibition of the increase in R(L) and 100% inhibition in the decrease in C-dyn; n = 4) Resolution of this compound gave (-)-14b, the most potent enantiomer (IC50 = 10 nM in the human 5-LO assay), which was shown to possess the S configuration at the chiral center by X-ray crystallographic analysis of an intermediate. Subsequent studies on the aryl thiopyrano[2,3,4-c,d]indole series of inhibitors led to the discovery of potent dual inhibitors of both FLAP and 5-LO, the most potent of which is 2-[[1-(4-chlorobenzyl)-4-methyl-6-(quinolin-2-ylmethoxy) -4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]methoxy]phenylacetic acid, 19. Acid 19 has an IC50 of 100 nM for the inhibition of 5-HPETE production by human 5-LO and is active in a FLAP binding assay with an IC50 of 32 nM. Furthermore, thiopyrano[2,3,4-c,d]indoles such as 1 and 14b are capable of inhibiting the LTC(4) synthase reaction in a dose dependent manner (IC(50)s of 11 and 16 mu M, respectively, compared to that of LTC(2) at 1.2 mu M) in contrast to other, structurally distinct 5-LO inhibitors. It has also been observed that the thiopyrano[2,3,4-c,d]indole class of compounds strongly promotes the translocation of 5-LO from the cytosol to a membrane fraction in the presence or absence of the ionophore A23187. The membrane-bound 5-LO retains its activity, and this association with the membrane is not reversed with the FLAP inhibitor MK-886. These observations, in part, support the hypothesis that these compounds act by binding at the arachidonic acid-binding site on FLAP, 5-LO, and LTC(4) synthase and that the thiopyrano[2,3,4-c,d]indole is capable of mimicking an active conformation of arachidonic acid.