拉索昔芬 | 180916-16-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 中文名称: 拉索昔芬
• 中文别名: (5R,6S)-5,6,7,8-四氢-6-苯基-5-(4-(2-(1-吡咯烷基)乙氧基)苯基)-2-萘酚
• 英文名称: lasofoxifene
• 英文别名: (-)-cis-(5R,6S)-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol；(5R,6S)-6-phenyl-5-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol；(5R,6S)-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl] 5,6,7,8-tetrahydronaphthalen-2-ol；(5R,6S)-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol；(6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol)
• CAS: 180916-16-9
• 化学式: C₂₈H₃₁NO₂
• 分子量: 413.56
• InChiKey: GXESHMAMLJKROZ-IAPPQJPRSA-N

物化性质

• 熔点：
  110-113°C
• 沸点：
  572.4±50.0 °C(Predicted)
• 密度：
  1.150±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  32.7
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

拉索昔芬的I相氧化主要通过肝脏中的CYP3A4/CYP3A5和CYP2D6进行，占总代谢的近一半。II相结合反应包括葡萄糖苷酸化和硫酸化。其葡萄糖苷酸化由在肝脏（UGT1A1、UGT1A3、UGT1A6和UGT1A9）和肠道（UGT1A8和UGT1A10）表达的UGT酶催化。在血浆中检测到的拉索昔芬进一步代谢物是羟基化代谢物的葡萄糖苷酸和甲基化儿茶酚。

Phase I oxidation via hepatic CYP3A4/CYP3A5 and CYP2D6 accounts for nearly half of total metabolism of lasofoxifene. Phase II conjugation reactions include glucuronidation and sulfation. Its glucuronidation is catalyzed by UGTs that are expressed in both the liver (UGT1A1, UGT1A3, UGT1A6, and UGT1A9) and the intestine (UGT1A8 and UGT1A10). Further metabolites of lasofoxifene detected in plasma are the glucuronide of a hydroxylated metabolite, and the methylated catechols.

来源:DrugBank

代谢

拉索foxifene 已知人类代谢物包括 (2S,3S,4S,5R)-3,4,5-三羟基-6-[[(5R,6S)-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-基]氧]氧杂环-2-羧酸。

Lasofoxifene has known human metabolites that include (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[[(5R,6S)-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-yl]oxy]oxane-2-carboxylic acid.

来源:NORMAN Suspect List Exchange

毒理性

• 蛋白质结合

拉索foxifene高度结合到血浆蛋白(>99%),其中它主要结合到白蛋白和α1-酸性糖蛋白。

Lasofoxifene is highly bound to plasma proteins (>99%) where it predominantly binds to albumin and α1-acid glycoprotein.

来源:DrugBank

吸收、分配和排泄

• 吸收

血浆峰浓度（Cmax）在大约6.0到7.3小时内达到。由于其非极性的四氢萘结构，增加了对肠道葡萄糖醛酸化的抵抗，显示出比其他SERMs更高的口服生物利用度。在大鼠的比较研究中，拉索昔芬显示出62%的生物利用度。

Peak plasma concentrations (Cmax) were reached in about 6.0 to 7.3 hours. Displays higher oral bioavailability compared to other SERMs with increased resistance to intestinal glucuronidation due to nonpolar tetrahydronaphthalene structure. In a comparative study in the rat, lasofoxifene showed bioavailability of 62%.

来源:DrugBank

吸收、分配和排泄

• 消除途径

主要经粪便排泄，其次为肾消除，主要以代谢物形式排出，少于2%以原型药物形式从尿液中排出。

Primarily fecal excretion and secondarily renal elimination as mainly metabolites, with less than 2% excreted in urine as unchanged parent drug.

来源:DrugBank

吸收、分配和排泄

• 分布容积

绝经后女性的表观分布容积为1350L。

The apparent volume of distribution in postmenopausal women is 1350L.

来源:DrugBank

吸收、分配和排泄

• 清除

绝经后妇女拉索昔芬的表观口服清除率（CL/F）约为6.6升/小时。

The apparent oral clearance (CL/F) of lasofoxifene in postmenopausal women is approximately 6.6 l/hr.

来源:DrugBank

制备方法与用途

拉索非芬（CP-336156）是一种口服活性且选择性的雌激素受体调节剂（SERM），具有抗骨质疏松的功能，并能抑制原发性肿瘤的生长和转移。这种药物可用于乳腺癌和绝经后骨质疏松症的研究。

反应信息

• 作为反应物：
  描述：

  拉索昔芬 以90% ee; 81的产率得到酒石酸拉索昔芬
  参考文献：
  名称：

  [EN] (-) CIS-6(S)-PHENYL-5(R)[4-(2-PYRROLIDIN-1-YLETHOXY)PHENYL]-5,6,7,8-TETRAHYDRONAPHTHALEN-2-OL D-TARTRATE
  [FR] (-) CIS-6(S)-PHENYL-5(R)[4-(2-PYRROLIDIN-1-YLETHOXY)PHENYL]-5,6,7,8-TETRAHYDRONYPHTHALEN-2-OL D-TARTRATE

  摘要：

  一种制备(-)顺式-6(S)-苯基-5(R)-[4-(2-吡咯啉-1-基乙氧)苯基]-5,6,7,8-四氢萘酚D-酒石酸盐的优越工艺。

  公开号：

  WO1997016434A1
• 作为产物：
  描述：

  CIS-1-[2-[4-(1,2,3,4-四氢-6-甲氧基-2-苯基-1-萘基)苯氧基]乙基]吡咯烷 以69的产率得到拉索昔芬
  参考文献：
  名称：

  [EN] (-) CIS-6(S)-PHENYL-5(R)[4-(2-PYRROLIDIN-1-YLETHOXY)PHENYL]-5,6,7,8-TETRAHYDRONAPHTHALEN-2-OL D-TARTRATE
  [FR] (-) CIS-6(S)-PHENYL-5(R)[4-(2-PYRROLIDIN-1-YLETHOXY)PHENYL]-5,6,7,8-TETRAHYDRONYPHTHALEN-2-OL D-TARTRATE

  摘要：

  一种制备(-)顺式-6(S)-苯基-5(R)-[4-(2-吡咯啉-1-基乙氧)苯基]-5,6,7,8-四氢萘酚D-酒石酸盐的优越工艺。

  公开号：

  WO1997016434A1

文献信息

• [EN] DIHYDROPYRROLONAPHTYRIDINONE COMPOUNDS AS INHIBITORS OF JAK<br/>[FR] COMPOSÉS DE DIHYDROPYRROLONAPHTYRIDINONE COMME INHIBITEURS DE JAK
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2010144486A1

  公开（公告）日：2010-12-16

  Disclosed are JAK inhibitors of formula (I) where G1, R1, R2, R3, R4, R5, R6, and R7 are defined in the specification. Also disclosed are pharmaceutical compositions, kits and articles of manufacture which contain the compounds, methods and materials for making the compounds, and methods of using the compounds to treat diseases, disorders, and conditions involving the immune system and inflammation, including rheumatoid arthritis, hematological malignancies, epithelial cancers (i.e., carcinomas), and other diseases, disorders or conditions associated with JAK.

  揭示了式(I)的JAK抑制剂，其中G1、R1、R2、R3、R4、R5、R6和R7在规范中定义。还披露了含有这些化合物的药物组合物、试剂盒和制造物品，制备这些化合物的方法和材料，以及使用这些化合物治疗涉及免疫系统和炎症的疾病、紊乱和症状的方法，包括类风湿关节炎、血液恶性肿瘤、上皮癌（即癌症）和其他与JAK相关的疾病、紊乱或症状。
• [EN] CATHEPSIN CYSTEINE PROTEASE INHIBITORS<br/>[FR] INHIBITEURS DE PROTÉASES À CYSTÉINE DE TYPE CATHEPSINES
  申请人：MERCK SHARP & DOHME

  公开号：WO2015054038A1

  公开（公告）日：2015-04-16

  This invention relates to a novel class of compounds which are cysteine protease inhibitors, including but not limited to, inhibitors of cathepsins K, L, S and B. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.

  这项发明涉及一类新型化合物，它们是半胱氨酸蛋白酶抑制剂，包括但不限于对卡特普辛K、L、S和B的抑制剂。这些化合物可用于治疗需要抑制骨吸收的疾病，如骨质疏松症。
• BRM TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE
  申请人：Arvinas Operations, Inc.

  公开号：US20190300521A1

  公开（公告）日：2019-10-03

  The present disclosure relates to bifunctional compounds, which find utility as modulators of SMARCA2 or BRM (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a ligand that binds to the Von Hippel-Lindau E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，其作为SMARCA2或BRM（靶蛋白）的调节剂具有实用性。具体而言，本公开涉及包含一端结合Von Hippel-Lindau E3泛素连接酶的配体，另一端结合靶蛋白的双功能化合物，使得靶蛋白与泛素连接酶靠近以实现靶蛋白的降解（和抑制）。本公开展示了与靶蛋白降解/抑制相关的广泛药理活性。本公开的化合物和组合物用于治疗或预防由靶蛋白聚集或积累导致的疾病或紊乱。
• [EN] ALANINE-BASED MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE<br/>[FR] MODULATEURS DE PROTÉOLYSE À BASE D'ALANINE ET PROCÉDÉS D'UTILISATION ASSOCIÉS
  申请人：ARVINAS INC

  公开号：WO2017011590A1

  公开（公告）日：2017-01-19

  The description relates to inhibitors of Apoptosis Proteins (TAPs) binding compounds, including Afunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the IAP E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.

  描述涉及抑制凋亡蛋白（TAPs）结合化合物，包括包含相同的A功能化合物，这些化合物作为靶向泛素化的调节剂发挥作用，特别是根据本发明的双功能化合物抑制各种多肽和其他蛋白质的化合物。具体而言，描述提供了一端含有结合到IAP E3泛素连接酶的配体，另一端含有结合到靶蛋白的基团的化合物，使得靶蛋白靠近泛素连接酶以促使该蛋白的降解（和抑制）。可以合成化合物，表现出与几乎任何类型的靶向多肽的降解/抑制一致的广泛药理活性。
• [EN] COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF BROMODOMAIN-CONTAINING PROTEINS<br/>[FR] COMPOSÉS ET PROCÉDÉS POUR LA DÉGRADATION CIBLÉE DE PROTÉINES CONTENANT UN BROMODOMAINE
  申请人：ARVINAS INC

  公开号：WO2017030814A1

  公开（公告）日：2017-02-23

  The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.

  本发明涉及双功能化合物，其作为靶向泛素化的调节剂具有实用性，特别是根据本发明抑制各种多肽和其他蛋白质的化合物。具体而言，本发明涉及一端含有结合泛素连接酶的VHL配体，另一端含有结合靶蛋白的基团的化合物，使得靶蛋白靠近泛素连接酶以促使该蛋白的降解（和抑制）。根据本发明的化合物表现出与靶向多肽的降解/抑制一致的广泛的药理活性。