(9S)-6,7,10,11-tetrahydro-9-{[(methylsulfonyl)oxy]methyl}-9H,18H-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13]-oxadiazacyclohexadecine-18,20(19H)-dione | 169940-46-9

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: (9S)-6,7,10,11-tetrahydro-9-{[(methylsulfonyl)oxy]methyl}-9H,18H-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13]-oxadiazacyclohexadecine-18,20(19H)-dione
• 英文别名: [(18S)-3,5-dioxo-17-oxa-4,14,21-triazahexacyclo[19.6.1.17,14.02,6.08,13.022,27]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaen-18-yl]methyl methanesulfonate
• CAS: 169940-46-9
• 化学式: C₂₇H₂₅N₃O₆S
• 分子量: 519.578
• InChiKey: GACYONFEVKQWRM-KRWDZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  37
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  117
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (9S)-6,7,10,11-tetrahydro-9-{[(methylsulfonyl)oxy]methyl}-9H,18H-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13]-oxadiazacyclohexadecine-18,20(19H)-dione 在 ammonium hydroxide 作用下， 以 1,4-二氧六环 为溶剂， 反应 24.0h， 生成 (S)-13-(aminomethyl)-10,11,14,15-tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-dione monohydrochloride
  参考文献：
  名称：

  (S)-13-[(Dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno- 1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-dione (LY333531) and Related Analogues:  Isozyme Selective Inhibitors of Protein Kinase Cβ

  摘要：

  Protein kinase C (PKC) is a family of closely related serine and threonine kinases. Overactivation of some PKC isozymes has been postulated to occur in several disease states, including diabetic complications. Selective inhibition of overactivated PKC isozymes may offer a unique therapeutic approach to disease states such as diabetic retinopathy. A novel series of 14-membered macrocycles containing a N-N'-bridged bisindolylmaleimide moiety is described. A panel of eight cloned human PKC isozymes (alpha, beta I, beta II, gamma, delta, epsilon, zeta, eta) was used to identify the series and optimize the structure and associated activity relationship. The dimethylamine analogue LY333531 (1), (S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-dione, inhibits the PKC beta I (IC50 = 4.7 nM) and PKC beta II (IC50 = 5.9 nM) isozymes and was 76- and 61-fold selective for inhibition of PKC beta I and PKC beta II in comparison to PKC alpha, respectively. The additional analogues described in the series are also selective inhibitors of PKC beta. LY333531 (1) exhibits ATP dependent competitive inhibition. of PKC beta I and is selective for PKC in comparison to other ATP dependent kinases (protein kinase A, calcium calmodulin, caesin kinase, src tyrosine kinase). The cellular activity of the series was assessed using bovine retinal capillary endothelial cells. Retinal endothelial cell dysfunction has been implicated in the development of diabetic retinopathy. Plasminogen activator activity stimulated by a phorbol ester (4 beta-phorbol 12,13-dibutyrate) in endothelial cells was inhibited by the compounds in the series with ED(50) values ranging from 7.5 to 0.21 mu M. A comparison of the PKC isozyme and related ATP dependent kinase inhibition profiles is provided for the series and compared to the profile for staurosporine, a nonselective PKC inhibitor. The cellular activity of the series is compared with that of the kinase inhibitor staurosporine.

  DOI：

  10.1021/jm950588y
• 作为产物：
  描述：

  tert-butyl-[(2S)-4-iodo-2-(2-iodoethoxy)butoxy]-diphenylsilane 在 吡啶 、 氢氧化钾 、 caesium carbonate 、 六甲基二硅氮烷 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 生成 (9S)-6,7,10,11-tetrahydro-9-{[(methylsulfonyl)oxy]methyl}-9H,18H-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13]-oxadiazacyclohexadecine-18,20(19H)-dione
  参考文献：
  名称：

  (S)-13-[(Dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno- 1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-dione (LY333531) and Related Analogues:  Isozyme Selective Inhibitors of Protein Kinase Cβ

  摘要：

  Protein kinase C (PKC) is a family of closely related serine and threonine kinases. Overactivation of some PKC isozymes has been postulated to occur in several disease states, including diabetic complications. Selective inhibition of overactivated PKC isozymes may offer a unique therapeutic approach to disease states such as diabetic retinopathy. A novel series of 14-membered macrocycles containing a N-N'-bridged bisindolylmaleimide moiety is described. A panel of eight cloned human PKC isozymes (alpha, beta I, beta II, gamma, delta, epsilon, zeta, eta) was used to identify the series and optimize the structure and associated activity relationship. The dimethylamine analogue LY333531 (1), (S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-dione, inhibits the PKC beta I (IC50 = 4.7 nM) and PKC beta II (IC50 = 5.9 nM) isozymes and was 76- and 61-fold selective for inhibition of PKC beta I and PKC beta II in comparison to PKC alpha, respectively. The additional analogues described in the series are also selective inhibitors of PKC beta. LY333531 (1) exhibits ATP dependent competitive inhibition. of PKC beta I and is selective for PKC in comparison to other ATP dependent kinases (protein kinase A, calcium calmodulin, caesin kinase, src tyrosine kinase). The cellular activity of the series was assessed using bovine retinal capillary endothelial cells. Retinal endothelial cell dysfunction has been implicated in the development of diabetic retinopathy. Plasminogen activator activity stimulated by a phorbol ester (4 beta-phorbol 12,13-dibutyrate) in endothelial cells was inhibited by the compounds in the series with ED(50) values ranging from 7.5 to 0.21 mu M. A comparison of the PKC isozyme and related ATP dependent kinase inhibition profiles is provided for the series and compared to the profile for staurosporine, a nonselective PKC inhibitor. The cellular activity of the series is compared with that of the kinase inhibitor staurosporine.

  DOI：

  10.1021/jm950588y

文献信息

• Synthesis and Characterization of the Selective, Reversible PKC_β Inhibitor (9<i>S</i>)-9-[(Dimethylamino)methyl]-6,7,10,11-tetrahydro-9<i>H</i>,18<i>H</i>-5,21:12,17-dimethenodibenzo[<i>e,k</i>]pyrrolo[3,4-<i>h</i>][1,4,13]oxadiazacyclohexadecine-18,20(19<i>H</i>)-dione, Ruboxistaurin (LY333531)
  作者：Anita H. Lewin、Larry Brieaddy、Jeffrey R. Deschamps、Gregory H. Imler、S. Wayne Mascarella、P. Anantha Reddy、F. Ivy Carroll

  DOI：10.1021/acschemneuro.8b00196

  日期：2019.1.16

  17-dimethenodibenzo[ e,k]pyrrolo[3,4- h][1,4,13]oxadiazacyclohexadecine-18,20(19 H)-dione, ruboxistaurin. Despite the interest in development of ruboxistaurin as the mesylate monohydrate (Arxxant) for the treatment of diabetic retinopathy, macular edema, and nephoropathy, several crucial details in physicochemical characterization were erroneous or missing. This report describes the synthesis and full characterization

  PKCβ在介导安非他明刺激的多巴胺流出中的调节作用，调节苯丙胺诱导的多巴胺转运蛋白的运输和活性，已证明促进了选择性可逆PKCβ抑制剂（9 S）-9-[（（二甲基氨基）甲基]- 6,7,10,11-四氢-9 H，18 H-5,21：12,17-二甲二苯并[e，k]吡咯并[3,4-h] [1,4,13]草二氮杂环十六烷-18,20 （19 H）-二酮，ruboxistaurin。尽管有兴趣开发鲁贝司他林作为甲磺酸盐一水合物（Arxxant）用于治疗糖尿病性视网膜病，黄斑水肿和肾病，但理化特性中的一些关键细节是错误的或缺失的。这份报告描述了Ruboxistaurin游离碱（作为一水合物）的合成和完整表征，包括X射线晶体学以确认其绝对构型，
• Macrocyclic Bisindolylmaleimides:  Synthesis by Inter- and Intramolecular Alkylation
  作者：Margaret M. Faul、Leonard L. Winneroski、Christine A. Krumrich、Kevin A. Sullivan、James R. Gillig、David A. Neel、Christopher J. Rito、Michael R. Jirousek

  DOI：10.1021/jo971980h

  日期：1998.3.1

  Macrocyclic bisindolylmaleimides 1-4 have been identified as competitive reversible inhibitors of PKC beta(1) and beta(2) and are being advanced to the clinic for evaluation as a treatment of retinopathy associated with diabetic complications. Highly convergent and stereoselective syntheses of 1-4 have been developed. The key synthetic step involves intermolecular alkylation of symmetrical bisindolylmaleimide 9 with chiral bisalkylating agent 8c and is amenable to the preparation of multikilogram quantities of these compounds. The synthetic sequence to 1, the most active compound, proceeds in 11 steps and 26% overall yield (>98% ee) from (R)-1-chloro-2,3-propanediol. No chromatographic purifications are required throughout the process and the final product is isolated in >97% purity after crystallization from DMF/MeOH. Synthesis of 1-4 by intramolecular alkylation proved less efficient, requiring 1? steps and affording 1-4 in lower overall yields of 6.0-8.5%.
• [EN] N-DESMETHYL RUBOXISTAURIN AS KINASE INHIBITOR<br/>[FR] N-DÉMÉTHYL RUBOXISTAURINE EN TANT QU'INHIBITEUR DE KINASE
  申请人：[en]4M THERAPEUTICS INC.

  公开号：WO2023192984A1

  公开（公告）日：2023-10-05

  Aspects of this invention are related to the use of N-desmethyl ruboxistaurin and pharmaceutically acceptable formulations thereof to modulate GSK3|3 signaling. Some aspects of the invention relate to the use of N-desmethyl ruboxistaurin to inhibit protein kinase C. Some aspects of the invention provide methods of using N-desmethyl ruboxistaurin in the treatment of subjects having a neurological disease and/or psychiatric disorder, including Alzheimer's disease, frontotemporal dementia, behavioral complications of dementia, bipolar disorder, depression, schizophrenia, Parkinson's disease, or neuroinflammation. Some aspects of this invention provide methods of using N-desmethyl ruboxistaurin in treating conditions associated with diabetes mellitus or its complications, or ischemia, inflammation, pulmonary hypertension, congestive heart failure, cardiovascular disease, dermatological disease, or cancer. Some aspects of the invention relate to the use of N-desmethyl ruboxistaurin as an alternative to ruboxistaurin, with a better pharmacokinetic profile, lower potential for prolongation of the electrocardiogram QT interval, and/or a lower potential for adverse drug interactions. In some embodiments, N-desmethyl ruboxistaurin is administered in combination with lithium or other treatments for bipolar disorder.
• (<i>S</i>)-13-[(Dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno- 1<i>H</i>,13<i>H</i>-dibenzo[<i>e</i>,<i>k</i>]pyrrolo[3,4-<i>h</i>][1,4,13]oxadiazacyclohexadecene-1,3(2<i>H</i>)-dione (LY333531) and Related Analogues:  Isozyme Selective Inhibitors of Protein Kinase Cβ
  作者：Michael R. Jirousek、James R. Gillig、Cecile M. Gonzalez、William F. Heath、John H. McDonald、David A. Neel、Christopher J. Rito、Upinder Singh、Lawrence E. Stramm、Anita Melikian-Badalian、Matthew Baevsky、Lawrence M. Ballas、Steven E. Hall、Leonard L. Winneroski、Margaret M. Faul

  DOI：10.1021/jm950588y

  日期：1996.1.1

  Protein kinase C (PKC) is a family of closely related serine and threonine kinases. Overactivation of some PKC isozymes has been postulated to occur in several disease states, including diabetic complications. Selective inhibition of overactivated PKC isozymes may offer a unique therapeutic approach to disease states such as diabetic retinopathy. A novel series of 14-membered macrocycles containing a N-N'-bridged bisindolylmaleimide moiety is described. A panel of eight cloned human PKC isozymes (alpha, beta I, beta II, gamma, delta, epsilon, zeta, eta) was used to identify the series and optimize the structure and associated activity relationship. The dimethylamine analogue LY333531 (1), (S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-dione, inhibits the PKC beta I (IC50 = 4.7 nM) and PKC beta II (IC50 = 5.9 nM) isozymes and was 76- and 61-fold selective for inhibition of PKC beta I and PKC beta II in comparison to PKC alpha, respectively. The additional analogues described in the series are also selective inhibitors of PKC beta. LY333531 (1) exhibits ATP dependent competitive inhibition. of PKC beta I and is selective for PKC in comparison to other ATP dependent kinases (protein kinase A, calcium calmodulin, caesin kinase, src tyrosine kinase). The cellular activity of the series was assessed using bovine retinal capillary endothelial cells. Retinal endothelial cell dysfunction has been implicated in the development of diabetic retinopathy. Plasminogen activator activity stimulated by a phorbol ester (4 beta-phorbol 12,13-dibutyrate) in endothelial cells was inhibited by the compounds in the series with ED(50) values ranging from 7.5 to 0.21 mu M. A comparison of the PKC isozyme and related ATP dependent kinase inhibition profiles is provided for the series and compared to the profile for staurosporine, a nonselective PKC inhibitor. The cellular activity of the series is compared with that of the kinase inhibitor staurosporine.