(±)-(3aR*，4S*，9bS*)-4-(6-溴-1,3-苯并二恶唑-5-基)-3a，4,5,9b-四氢-8-(1-甲基乙基)-3H-环戊[C]喹啉 | 1392487-51-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 中文名称: (±)-(3aR*，4S*，9bS*)-4-(6-溴-1,3-苯并二恶唑-5-基)-3a，4,5,9b-四氢-8-(1-甲基乙基)-3H-环戊[C]喹啉
• 英文名称: G-36
• 英文别名: 4-(6-bromobenzo[1,3]dioxol-5-yl)-8-isopropyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline；endo-G36；(3aS,4R,9bR)-4-(6-bromo-1,3-benzodioxol-5-yl)-8-propan-2-yl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline
• CAS: 1392487-51-2
• 化学式: C₂₂H₂₂BrNO₂
• 分子量: 412.326
• InChiKey: QTOCPACSSHFGOY-ZCCHDVMBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  30.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  4-异丙基苯胺 、 6-溴-3,4-亚甲基二氧苯甲醛 、 环戊二烯 在 scandium tris(trifluoromethanesulfonate) 作用下， 以 乙腈 为溶剂， 反应 2.0h， 以94%的产率得到(±)-(3aR*，4S*，9bS*)-4-(6-溴-1,3-苯并二恶唑-5-基)-3a，4,5,9b-四氢-8-(1-甲基乙基)-3H-环戊[C]喹啉
  参考文献：
  名称：

  Identification of a GPER/GPR30 antagonist with improved estrogen receptor counterselectivity

  摘要：

  GPER/GPR30 is a seven-transmembrane G protein-coupled estrogen receptor that regulates many aspects of mammalian biology and physiology. We have previously described both a GPER-selective agonist G-1 and antagonist G15 based on a tetrahydro-3H-cyclopenta[c]quinoline scaffold. The antagonist lacks an ethanone moiety that likely forms important hydrogen bonds involved in receptor activation. Computational docking studies suggested that the lack of the ethanone substituent in G15 could minimize key steric conflicts, present in G-1, that limit binding within the ER alpha ligand binding pocket. In this report, we identify low-affinity cross-reactivity of the GPER antagonist G15 to the classical estrogen receptor ER alpha. To generate an antagonist with enhanced selectivity, we therefore synthesized an isosteric G-1 derivative, G36, containing an isopropyl moiety in place of the ethanone moiety. We demonstrate that G36 shows decreased binding and activation of ER alpha, while maintaining its antagonist profile towards GPER. G36 selectively inhibits estrogen-mediated activation of PI3K by GPER but not ER alpha. It also inhibits estrogen- and G-1-mediated calcium mobilization as well as ERK1/2 activation, with no effect on EGF-mediated ERK1/2 activation. Similar to G15, G36 inhibits estrogen- and G-1-stimulated proliferation of uterine epithelial cells in vivo. The identification of G36 as a GPER antagonist with improved ER counterselectivity represents a significant step towards the development of new highly selective therapeutics for cancer and other diseases. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.jsbmb.2011.07.002

文献信息

• Compositions and methods for decreasing, or preventing or reversing gain of, skin pigmentation in a mammalian subject
  申请人：THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA

  公开号：US11236074B2

  公开（公告）日：2022-02-01

  The present invention includes compounds, compositions comprising the same, and methods using the compounds and/or compositions therein, for modulating skin pigmentation in a mammalian subject. In certain embodiments, the compounds of the invention treat or prevent skin disorders or diseases associated with hyperpigmentation in the subject. In other embodiments, the compounds of the invention act as antagonist to the non-canonical sex steroid hormone receptor GPRE1 and do not bind to a canonical nuclear estrogen receptor (ER). In yet other embodiments, the compounds of the invention comprise acts as agonists to the non-canonical sex steroid hormone receptor PAQR7 and do not bind to a canonical nuclear progesterone receptor (PR).

  本发明包括用于调节哺乳动物皮肤色素沉着的化合物、包含这些化合物的组合物以及使用这些化合物和/或组合物的方法。在某些实施方案中，本发明的化合物可治疗或预防与受试者色素沉着相关的皮肤失调或疾病。在其他实施方案中，本发明化合物作为非典型性类固醇激素受体 GPRE1 的拮抗剂，不与典型核雌激素受体（ER）结合。在另一些实施方案中，本发明的化合物包括作为非典型性类固醇激素受体 PAQR7 的激动剂，并且不与典型的核黄体酮受体（PR）结合。
• COMPOSITIONS AND METHODS FOR DECREASING, OR PREVENTING OR REVERSING GAIN OF, SKIN PIGMENTATION IN A MAMMALIAN SUBJECT
  申请人：THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA

  公开号：US20220017497A1

  公开（公告）日：2022-01-20

  The present invention includes compounds, compositions comprising the same, and methods using the compounds and/or compositions therein, for modulating skin pigmentation in a mammalian subject. In certain embodiments, the compounds of the invention treat or prevent skin disorders or diseases associated with hyperpigmentation in the subject. In other embodiments, the compounds of the invention act as antagonist to the non-canonical sex steroid hormone receptor GPRE1 and do not bind to a canonical nuclear estrogen receptor (ER). In yet other embodiments, the compounds of the invention comprise acts as agonists to the non-canonical sex steroid hormone receptor PAQR7 and do not bind to a canonical nuclear progesterone receptor (PR).