(S,Z)-N-(3-(4-(2-(5-甲基-2-苯基恶唑-4-基)乙氧基)苯基)-2-((4-氧代-4-(4-(三氟甲基)苯基)丁-2-烯-2-基)氨基)丙基)丙酰胺 | 880635-03-0

• 物质功能分类: 生物化工 - 抑制剂 - 代谢(Metabolism)
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 中文名称: (S,Z)-N-(3-(4-(2-(5-甲基-2-苯基恶唑-4-基)乙氧基)苯基)-2-((4-氧代-4-(4-(三氟甲基)苯基)丁-2-烯-2-基)氨基)丙基)丙酰胺
• 英文名称: GW 6471
• 英文别名: N-[(2S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-[[(Z)-4-oxo-4-[4-(trifluoromethyl)phenyl]but-2-en-2-yl]amino]propyl]propanamide
• CAS: 880635-03-0
• 化学式: C₃₅H₃₆F₃N₃O₄
• 分子量: 619.7
• InChiKey: TYEFSRMOUXWTDN-DYQICHDWSA-N

物化性质

• 密度：
  1.204±0.06 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：15 毫克/毫升

计算性质

• 辛醇/水分配系数(LogP)：
  7.9
• 重原子数：
  45
• 可旋转键数：
  14
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  93.5
• 氢给体数：
  2
• 氢受体数：
  9

安全信息

• 危险品标志：
  Xi
• 安全说明：
  S26,S36
• 危险类别码：
  R36/37/38
• WGK Germany：
  3
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

用途

GW 6471是有效的PPARα拮抗剂，IC50为0.24 μM。

靶点

Target: PPARα (Cell-free assay)
IC50: 0.24 μM

作用机制

GW6471能完全抑制GW409544诱导的PPARα激活反应，IC50为0.24 μM。在浓度介于0.001-10 μM之间的范围内，GW6471会破坏PPAR与来源于SRC-1或CBP的共激活基元之间的相互作用，并促进来自SMRT或N-CoR的共抑制基元结合。该化合物以U形配置缠绕在螺旋3的C276上，破坏了电荷钳的完整性，但仍允许共阻遏基序中的额外螺旋形旋转。

浓度为10 μM的GW6471能够以时间依赖性的方式显著阻止心肌细胞分化，并导致心脏肌节蛋白（如α-肌动蛋白、肌钙蛋白-T）和特定基因（如α-MHC、MLC2v）的表达降低，这主要是通过抑制PPARα实现的。

生物活性

GW 6471是一种有效的PPARα拮抗剂，其IC50值为0.24 μM。

文献信息

• PROPHYLACTIC AGENT AND/OR THERAPEUTIC AGENT FOR CATARACT, MEDICINAL COMPOSITION FOR PREVENTING AND/OR TREATING CATARACT, USE OF PPAR ACTIVATOR FOR PRODUCING SAME, AND EYEDROPS
  申请人：University of Fukui

  公开号：EP3733203A1

  公开（公告）日：2020-11-04

  Provided are agents for prevention and therapeutic treatment of cataract that act by a different mechanism from conventional agents, and use of a PPAR activator for production of such agents. An agent for prevention and/or therapeutic treatment of cataract, containing a PPAR activator as an active ingredient, is used.

  本发明提供了预防和治疗白内障的药剂，其作用机理与传统药剂不同，还提供了使用 PPAR 激活剂生产此类药剂的方法。一种用于预防和/或治疗白内障的药剂含有 PPAR 激活剂作为活性成分。
• CENICRIVIROC COMBINATION THERAPY FOR THE TREATMENT OF FIBROSIS
  申请人：Tobira Therapeutics, Inc.

  公开号：EP3777863A1

  公开（公告）日：2021-02-17

  Cenicriviroc (CVC) is an orally active antagonist of ligand binding to C-C chemokine receptor type 5 (CCR5) and C-C chemokine receptor type 2 (CCR2). CVC blocks the binding of RANTES, MIP-1α, and MIP-1β to CCR5, and of MCP-1/CCL2 to CCR2. Methods of treating fibrosis and related conditions comprising co-administration of CVC with FXR agonists, high dose vitamin E (>400 iU/d), a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, PPAR-γ agonist, PPAR-δ agonist and/or chemokine antagonists are provided herein.

  Cenicriviroc (CVC) 是一种口服活性拮抗剂，能抑制配体与 C-C 趋化因子受体 5 型 (CCR5) 和 C-C 趋化因子受体 2 型 (CCR2) 的结合。CVC 可阻断 RANTES、MIP-1α 和 MIP-1β 与 CCR5 的结合，以及 MCP-1/CCL2 与 CCR2 的结合。本文提供了治疗纤维化及相关疾病的方法，包括将 CVC 与 FXR 激动剂、高剂量维生素 E（>400 iU/d）、过氧化物酶体增殖激活受体α（PPAR-α）激动剂、PPAR-γ 激动剂、PPAR-δ 激动剂和/或趋化因子拮抗剂联合给药。
• Targeting metabolic adaptive responses to chemotherapy
  申请人：University of Cincinnati

  公开号：US10835519B2

  公开（公告）日：2020-11-17

  Methods for targeting adaptive responses to chemotherapy are described. In various embodiments, a method comprises administering at least one compound that inhibits S6K1, mTORC1 or upstream or downstream pathway components of S6K1 or mTORC1, in association with administration of at least one inhibitor of PPARα, PPARδ, or PGC1α. In various embodiments, the compound that inhibits S6K1, mTORC1, or upstream or downstream pathway components of S6K1 or mTORC1 is rapamycin, everolimus, temsirolimus, or imatinib. The inhibitor of PPARα, PPARδ, or PGC1α can be an antagonist or an inverse agonist selected from GW6471, GSK3787, GSK0660, and ST247.

  本文描述了针对化疗适应性反应的方法。在不同的实施方案中，一种方法包括在施用至少一种 PPARα、PPARδ或 PGC1α 抑制剂的同时，施用至少一种抑制 S6K1、mTORC1 或 S6K1 或 mTORC1 的上游或下游通路成分的化合物。在各种实施方案中，抑制 S6K1、mTORC1 或 S6K1 或 mTORC1 的上游或下游通路成分的化合物是雷帕霉素、依维莫司、替西洛莫司或伊马替尼。PPARα、PPARδ或PGC1α的抑制剂可以是选自GW6471、GSK3787、GSK0660和ST247的拮抗剂或反向激动剂。
• Targeting Metabolic Adaptive Responses to Chemotherapy
  申请人：UNIVERSITY OF CINCINNATI

  公开号：US20130203769A1

  公开（公告）日：2013-08-08

  Methods for targeting adaptive responses to chemotherapy are described. In various embodiments, a method comprises administering at least one compound that inhibits S6K1, mTORC, or upstream or downstream pathway components of S6K1 or mTORC, in association with administration of at least one antagonist of PPARα, PPARδ, or PGC1α. In various embodiments, the compound that inhibits S6K1, mTORC, or upstream or downstream pathway components of S6K1 or mTORC is rapamycin, everolimus, temsirolimus, or imatinib. The antagonist of PPARα, PPARδ, or PGC1α can be GW7647, GW6471, GW501516, GSK3787, or GSK0660.
• THERAPEUTIC COMPOUNDS THAT SUPPRESS PROTEIN ARGININE METHYLTRANSFERASE ACTIVITY FOR REDUCING TUMOR CELL PROLIFERATION
  申请人：Epinova Therapeutics Corp.

  公开号：US20160271149A1

  公开（公告）日：2016-09-22

  The described invention provides methods for modulating gene expression of a gene related to proliferation of a population of tumor cells. The method entails administering a therapeutic amount of a therapeutic compound to a cell, a tissue, or a mammal, wherein the therapeutic amount of the therapeutic compound is effective to suppress methyltransferase activity of a protein arginine methyltransferase. Modulation of the protein arginine methyltransferase activity in turn modulates methylation of a target protein that affects gene expression of the gene, and may suppress the proliferation of the population of tumor cells.