[(8R)-3-[2-(2,4-difluorophenyl)thiazol-4-yl]-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl][4-(2-thienyl)phenyl]methanone | 1338373-68-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 三唑并吡嗪类
• 英文名称: [(8R)-3-[2-(2,4-difluorophenyl)thiazol-4-yl]-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl][4-(2-thienyl)phenyl]methanone
• 英文别名: (R)-(3-(2-(2,4-difluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone；[(8R)-3-[2-(2,4-difluorophenyl)-1,3-thiazol-4-yl]-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-(4-thiophen-2-ylphenyl)methanone
• CAS: 1338373-68-4
• 化学式: C₂₆H₁₉F₂N₅OS₂
• 分子量: 519.599
• InChiKey: ZSIQAOCNFRWDNJ-OAHLLOKOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  36
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  120
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine 在 N-甲基吗啉 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 9.42h， 生成 [(8R)-3-[2-(2,4-difluorophenyl)thiazol-4-yl]-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl][4-(2-thienyl)phenyl]methanone
  参考文献：
  名称：

  Discovery and Optimization of Novel Antagonists to the Human Neurokinin-3 Receptor for the Treatment of Sex-Hormone Disorders (Part I)

  摘要：

  Neurokinin-3 receptor (NK3R) has recently emerged as important in modulating the tonic pulsatile gonadotropin-releasing hormone (GnRH) release. We therefore decided to explore NK3R antagonists as therapeutics for sex-hormone disorders that can potentially benefit from lowering GnRH pulsatility with consequent diminished levels of plasma luteinizing hormone (LH) and correspondingly attenuated levels of circulating androgens and estrogens. The discovery and lead optimization of a novel N-acyl-triazolopiperazine NK3R antagonist chemotype achieved through bioisosteric lead change from the high-throughput screening (HTS) hit is described. A concomitant improvement in the antagonist bioactivity and ligand lipophilic efficiency (LLE) parameter were the principal guidelines in the lead optimization efforts. Examples of advanced lead analogues to demonstrate the amenability of this chemotype to achieving a suitable pharmacokinetic (PK) profile are provided as well as pharmacokinetic-pharmacodynamic (PKPD) correlations to analyze the trends observed for LH inhibition in castrated rats and monkeys that served as preliminary in vivo efficacy models.

  DOI：

  10.1021/jm5017413

文献信息

• [EN] NOVEL NK-3 RECEPTOR SELECTIVE ANTAGONIST COMPOUNDS, PHARMACEUTICAL COMPOSITION AND METHODS FOR USE IN NK-3 RECEPTORS MEDIATED DISORDERS<br/>[FR] NOUVEAUX COMPOSÉS ANTAGONISTES SÉLECTIFS DU RÉCEPTEUR NK-3, COMPOSITION PHARMACEUTIQUE ET MÉTHODES POUR UNE UTILISATION DANS DES TROUBLES À MÉDIATION PAR DES RÉCEPTEURS NK-3
  申请人：EUROSCREEN SA

  公开号：WO2011121137A1

  公开（公告）日：2011-10-06

  The present invention is directed to novel compounds of formula I and their use as therapeutic compounds.

  本发明涉及公式I的新化合物及其作为治疗化合物的用途。
• NOVEL NK-3 RECEPTOR SELECTIVE ANTAGONIST COMPOUNDS, PHARMACEUTICAL COMPOSITION AND METHODS FOR USE IN NK-3 RECEPTORS MEDIATED DISORDERS
  申请人：Euroscreen S.A.

  公开号：US20130023530A1

  公开（公告）日：2013-01-24

  The present invention is directed to novel compounds of formula I and their use as therapeutic compounds.

  本发明涉及一种新型化合物I的使用作为治疗化合物。
• NK-3 receptor selective antagonist compounds, pharmaceutical composition and methods for use in NK-3 receptors mediated disorders
  申请人：Ogeda SA

  公开号：US10065960B2

  公开（公告）日：2018-09-04

  The present invention is directed to novel compounds of formula I and their use as therapeutic compounds.

  本发明涉及式 I 的新型化合物 及其作为治疗化合物的用途。
• NK-3 receptor antagonists for therapeutic or cosmetic treatment of excess body fat
  申请人：OGEDA SA

  公开号：US10624890B2

  公开（公告）日：2020-04-21

  Disclosed is use of NK3R antagonists for the therapeutic treatment of pathological excess body fat and/or prevention of body fat gain in patients. Also disclosed is a cosmetic method for stimulating the loss of excess of body fat, including the administration of a NK-3 receptor antagonist.

  本发明公开了 NK3R 拮抗剂在治疗病理性体脂过多和/或预防患者体脂增加方面的用途。还公开了一种刺激减少体内多余脂肪的美容方法，包括施用 NK-3 受体拮抗剂。
• NK-3 RECEPTOR ANTAGONISTS FOR THERAPEUTIC OR COSMETIC TREATMENT OF EXCESS BODY FAT
  申请人：OGEDA SA

  公开号：US20180289705A1

  公开（公告）日：2018-10-11

  Disclosed is use of NK3R antagonists for the therapeutic treatment of pathological excess body fat and/or prevention of body fat gain in patients. Also disclosed is a cosmetic method for stimulating the loss of excess of body fat, including the administration of a NK-3 receptor antagonist.