(R)-1-Boc-3-((2-(trifluoromethyl)phenoxy)methyl)pyrrolidine

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (R)-1-Boc-3-((2-(trifluoromethyl)phenoxy)methyl)pyrrolidine
• 英文别名: tert-butyl (3R)-3-[[2-(trifluoromethyl)phenoxy]methyl]pyrrolidine-1-carboxylate
• 化学式: C₁₇H₂₂F₃NO₃
• 分子量: 345.362
• InChiKey: CDUICEUGUOMYLO-GFCCVEGCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  38.8
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (R)-1-Boc-3-((2-(trifluoromethyl)phenoxy)methyl)pyrrolidine 在 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 32.0h， 生成 methyl (R)-6-methyl-2-(3-((2-(trifluoromethyl)phenoxy)methyl)pyrrolidin-1-yl) pyrimidine-4-carboxylic acid
  参考文献：
  名称：

  Discovery of Bispecific Antagonists of Retinol Binding Protein 4 That Stabilize Transthyretin Tetramers: Scaffolding Hopping, Optimization, and Preclinical Pharmacological Evaluation as a Potential Therapy for Two Common Age-Related Comorbidities

  摘要：

  Accumulation of cytotoxic lipofuscin bisretinoids may contribute to atrophic age-related macular degeneration (AMD) pathogenesis. Retinal bisretinoid synthesis depends on the influx of serum all-trans-retinol (1) delivered via a tertiary retinol binding protein 4 (RBP4)-transthyretin (TTR)-retinol complex. We previously identified selective RBP4 antagonists that dissociate circulating RBP4-TTR-retinol complexes, reduce serum RBP4 levels, and inhibit bisretinoid synthesis in models of enhanced retinal lipofuscinogenesis. However, the release of TTR by selective RBP4 antagonists may be associated with TTR tetramer destabilization and, potentially, TTR amyloid formation. We describe herein the identification of bispecific RBP4 antagonist-TTR tetramer kinetic stabilizers. Standout analogue (+/-)-44 possesses suitable potency for both targets, significantly lowers mouse plasma RBP4 levels, and prevents TTR aggregation in a gel-based assay. This new class of bispecific compounds may be especially important as a therapy for dry AMD patients who have another common age-related comorbidity, senile systemic amyloidosis, a nongenetic disease associated with wild-type TTR misfolding.

  DOI：

  10.1021/acs.jmedchem.0c00996
• 作为产物：
  描述：

  (R)-1-Boc-3-羟甲基吡咯烷 在 4-二甲氨基吡啶 、 caesium carbonate 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 32.0h， 生成 (R)-1-Boc-3-((2-(trifluoromethyl)phenoxy)methyl)pyrrolidine
  参考文献：
  名称：

  Discovery of Bispecific Antagonists of Retinol Binding Protein 4 That Stabilize Transthyretin Tetramers: Scaffolding Hopping, Optimization, and Preclinical Pharmacological Evaluation as a Potential Therapy for Two Common Age-Related Comorbidities

  摘要：

  Accumulation of cytotoxic lipofuscin bisretinoids may contribute to atrophic age-related macular degeneration (AMD) pathogenesis. Retinal bisretinoid synthesis depends on the influx of serum all-trans-retinol (1) delivered via a tertiary retinol binding protein 4 (RBP4)-transthyretin (TTR)-retinol complex. We previously identified selective RBP4 antagonists that dissociate circulating RBP4-TTR-retinol complexes, reduce serum RBP4 levels, and inhibit bisretinoid synthesis in models of enhanced retinal lipofuscinogenesis. However, the release of TTR by selective RBP4 antagonists may be associated with TTR tetramer destabilization and, potentially, TTR amyloid formation. We describe herein the identification of bispecific RBP4 antagonist-TTR tetramer kinetic stabilizers. Standout analogue (+/-)-44 possesses suitable potency for both targets, significantly lowers mouse plasma RBP4 levels, and prevents TTR aggregation in a gel-based assay. This new class of bispecific compounds may be especially important as a therapy for dry AMD patients who have another common age-related comorbidity, senile systemic amyloidosis, a nongenetic disease associated with wild-type TTR misfolding.

  DOI：

  10.1021/acs.jmedchem.0c00996

文献信息

• [EN] SALT FORM CRYSTAL FORM OF PYRIMIDINE DERIVATIVE AND PREPARATION METHOD THEREFOR<br/>[FR] FORME CRISTALLINE SOUS FORME DE SEL DE DÉRIVÉ DE PYRIMIDINE ET SON PROCÉDÉ DE PRÉPARATION<br/>[ZH] 一种嘧啶衍生物盐型晶型及制备方法
  申请人：[en]SCIMOUNT BIOTECHNOLOGY (SHENZHEN) CO., LTD.;[zh]科岭源生物科技（深圳）有限公司

  公开号：WO2023138592A1

  公开（公告）日：2023-07-27

  本发明提供了一种嘧啶衍生物盐型晶型及制备方法，属于化学领域。所述嘧啶衍生物的晶型为式(I)所示嘧啶衍生物的乙醇胺盐晶型A、叔丁胺盐晶型A、叔丁胺盐晶型B、葡甲胺盐晶型A、钾盐晶型A、镁盐晶型A、镁盐晶型B、钙盐晶型A、氢溴酸盐晶型A、氢溴酸盐晶型B、氢溴酸盐晶型C、氢溴酸盐晶型D或L-精氨酸盐晶型A。本发明嘧啶衍生物的盐型晶型稳定性好，溶解度佳，生物利用度高，药效优异，安全性好。与式(I)所示嘧啶衍生物相比，综合性能显著提高，有利于药物加工和使用，为固体药物的疗效及安全性研究提供了更多的定性定量信息，具有优异的应用前景。