(3R)-N-hydroxy-2-((4-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (3R)-N-hydroxy-2-((4-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
• 英文别名: MMP-8 inhibitor I；(3R)-(+)-2-(4-methoxybenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamate；(3R)-N-hydroxy-2-(4-methoxyphenyl)sulfonyl-3,4-dihydro-1H-isoquinoline-3-carboxamide
• 化学式: C₁₇H₁₈N₂O₅S
• 分子量: 362.406
• InChiKey: PPELJLBDXLMTEW-MRXNPFEDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  104
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  (R)-(+)-1,2,3,4-四氢异喹啉-3-羧酸 在 N-乙基马来酰亚胺 、 sodium hydroxide 、 氯甲酸乙酯 作用下， 以 四氢呋喃 为溶剂， 生成 (3R)-N-hydroxy-2-((4-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
  参考文献：
  名称：

  Tetrahydroisoquinoline-3-carboxylate based matrix-metalloproteinase inhibitors: design, synthesis and structure–activity relationship

  摘要：

  The design, synthesis and structure-activity relationship (SAR) of a series of nonpeptidic 2-arylsulfonyl-1,2,3,4-tetra-hydro-isoquinoline-3-carboxylates and-hydroxamates as inhibitors of the matrix metalloproteinase human neutrophil collagenase (MMP-8) is described here. Based on available X-ray structures of MMP-8/inhibitor complexes, our structure-based design strategy was directed to complement major protein-ligand interaction regions mainly in the S1' hydrophobic specificity pocket close to the catalytic zinc ion. Here, the rigid 1,2,3,4-tetrahydroisoquinoline scaffold (Tic) provides ideal geometry to combine hydroxamates and carboxylates as typical zinc complexing functionalities, with a broad variety of S1' directed mono- and biaryl substituents consisting of aromatic rings perfectly accommodated within this more hydrophobic region of the MMP-8 inhibitor binding site. The effect of different S1' directed substituents, zinc-complexing groups, chirality and variations of the tetrahydroisoquinoline ring-system is investigated by systematic studies. X-ray structure analyses in combination with 3D-QSAR studies provided an additional understanding of key determinants for MMP-8 affinity in this series. The hypothetical binding mode for a typical molecule as basis for our inhibitor design was found in good agreement with a 1.7 Angstrom X-ray structure of this candidate in complex with the catalytic domain of human MMP-8. After analysis of all systematic variations, 3D-QSAR and X-ray structure analysis, novel S1' directed substituents were designed and synthesized and biologically evaluated. This finally results in inhibitors, which do not only show high biological affinity for MMP-8, but also exhibit good oral bioavailability in several animal species. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(02)00215-8

文献信息

• Characterization of a selective inhibitor for matrix metalloproteinase-8 (MMP-8)
  作者：Derong Ding、Katerina Lichtenwalter、Hualiang Pi、Shahriar Mobashery、Mayland Chang

  DOI：10.1039/c4md00172a

  日期：——

  MMP-8 has been implicated in various diseases. Selective MMP-8 inhibitors are needed to ascertain the role of this enzyme. We synthesized two inhibitors reported previously as selective for MMP-8. Compound 1 selectively inhibited MMP-8 and MMP-13; compound 2 was a potent broad-spectrum inhibitor, notwithstanding that it is used as a selective one.

  MMP-8与多种疾病有关。需要选择性的MMP-8抑制剂来确定这种酶的作用。我们合成了两种先前报道的对MMP-8具有选择性的抑制剂。化合物1选择性抑制MMP-8和MMP-13；化合物2是有效的广谱抑制剂，尽管它被用作选择性抑制剂。
• Stimulation of pancreatic beta-cell proliferation
  申请人：THE ROCKEFELLER UNIVERSITY

  公开号：EP2605013A1

  公开（公告）日：2013-06-19

  This invention provides a polypeptide, TMEM27, and secreted forms thereof, nucleic acids and constructs encoding the same, and cells comprising the same. The TMEM27 protein is expressed in hormone positive cells at early stages of pancreas development and pancreatic beta-cells in the mature pancreas, whose expression promotes pancreatic beta-cell replication and increased islet mass. Applications of the protein in diagnostics and therapeutics are described.

  本发明提供了一种多肽 TMEM27 及其分泌形式、编码该多肽的核酸和构建体以及包含该多肽的细胞。TMEM27 蛋白在胰腺发育早期的激素阳性细胞和成熟胰腺的胰岛β细胞中表达，其表达可促进胰岛β细胞的复制和胰岛质量的增加。本文介绍了该蛋白在诊断和治疗中的应用。
• Methods for production of platelets from pluripotent stem cells and compositions thereof
  申请人：Ocata Therapeutics, Inc.

  公开号：US10426799B2

  公开（公告）日：2019-10-01

  Methods for production of platelets from pluripotent stem cells, such as human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) are provided. These methods may be performed without forming embryoid bodies or clusters of pluripotent stem cells, and may be performed without the use of stromal inducer cells. Additionally, the yield and/or purity can be greater than has been reported for prior methods of producing platelets from pluripotent stem cells. Also provided are compositions and pharmaceutical preparations comprising platelets, preferably produced from pluripotent stem cells.

  提供了利用多能干细胞（如人类胚胎干细胞（hESC）和诱导多能干细胞（iPSC））生产血小板的方法。这些方法可以在不形成胚状体或多能干细胞簇的情况下进行，也可以在不使用基质诱导细胞的情况下进行。此外，其产量和/或纯度可高于先前报道的用多能干细胞生产血小板的方法。此外，还提供了包含血小板的组合物和药物制剂，最好是由多能干细胞制备的血小板。
• Compounds and methods for the modulation of CD154
  申请人：——

  公开号：US20020165166A1

  公开（公告）日：2002-11-07

  The present invention relates to compounds that are capable of modulating CD154 mobilization and that are useful for stabilizing the thrombotic process and reducing the activation of cells involved in an inflammatory response. The present invention also relates to methods useful for identifying such compounds. The present invention also relates to the treatment of platelets for transfusion with metalloproteinase inhibitors to treat or prevent inflammation. The present invention also includes compositions and methods to treat injury and disease related to such biological processes.

  本发明涉及能够调节 CD154 调动的化合物，这些化合物可用于稳定血栓形成过程和减少参与炎症反应的细胞的活化。本发明还涉及用于鉴定此类化合物的方法。本发明还涉及用金属蛋白酶抑制剂处理输血用血小板，以治疗或预防炎症。本发明还包括治疗与此类生物过程有关的损伤和疾病的组合物和方法。
• Compositions, methods and kits relating to Her-2 cleavage
  申请人：——

  公开号：US20040247602A1

  公开（公告）日：2004-12-09

  The present invention relates to compositions, methods and kits based on the ADAM-mediated cleavage of Her-2. The present invention also relates to treatments for cancer, and in particular, breast cancer, by modulating the ADAM-mediated cleavage of Her-2. Further, the invention relates to compositions, methods and kits based on the surprising synergistic effect between inhibition of Her-2 cleavage by an ADAM and certain cytostatic (e.g., Herceptin) and cytotoxic (e.g., Taxol) compounds in, among other things, inhibiting tumor cell proliferation and inducing cell death. Additionally, the invention relates to novel variants of ADAM15, designated ADAM15 variant 1 and ADAM15 variant 2, now identified and isolated.

  本发明涉及基于ADAM介导的Her-2裂解的组合物、方法和试剂盒。本发明还涉及通过调节 ADAM 介导的 Her-2 的裂解来治疗癌症，特别是乳腺癌。此外，本发明还涉及组合物、方法和试剂盒，这些组合物、方法和试剂盒基于通过 ADAM 抑制 Her-2 的裂解与某些细胞抑制剂（如赫赛汀）和细胞毒性（如 Taxol）化合物在抑制肿瘤细胞增殖和诱导细胞死亡等方面惊人的协同效应。此外，本发明还涉及现已鉴定和分离出的 ADAM15 的新型变体，即 ADAM15 变体 1 和 ADAM15 变体 2。