(S)-2-甲基-N-(4-硝基-3-(三氟甲基)苯基)环氧乙烷-2-甲酰胺 | 348597-81-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: (S)-2-甲基-N-(4-硝基-3-(三氟甲基)苯基)环氧乙烷-2-甲酰胺
• 英文名称: (S)-N-(4-nitro-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide
• 英文别名: (S)-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)oxirane-2-carboxamide；(S)-N-[3-(Trifluoromethyl)-4-nitrophenyl]-2-methyloxirane-2-carboxamide；(2S)-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]oxirane-2-carboxamide
• CAS: 348597-81-9
• 化学式: C₁₁H₉F₃N₂O₄
• 分子量: 290.199
• InChiKey: MXYYQYGACYMJDH-JTQLQIEISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  87.4
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (S)-2-甲基-N-(4-硝基-3-(三氟甲基)苯基)环氧乙烷-2-甲酰胺 在 水 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 以80%的产率得到(S)-2,3-dihydroxy-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide
  参考文献：
  名称：

  Novel pathway for the synthesis of arylpropionamide-derived selective androgen receptor modulator (SARM) metabolites of andarine and ostarine

  摘要：

  O-Dephenylandarine and O-dephenylostarine, two SARM metabolites relevant for doping control analysis, were synthesized in their endogenous (S)-forms as well as in terms of their racemates. The enantiopure (S)-metabolites were obtained after six steps in 20% and 23% overall yield, the slightly modified racemic route provided the compounds in 28% and 31% total yield, respectively. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetlet.2013.02.065
• 作为产物：
  描述：

  5-氨基-2-硝基三氟甲苯 在 氯化亚砜 、 potassium carbonate 作用下， 以 四氢呋喃 、 丁酮 为溶剂， 反应 6.0h， 生成 (S)-2-甲基-N-(4-硝基-3-(三氟甲基)苯基)环氧乙烷-2-甲酰胺
  参考文献：
  名称：

  吡唑-1-基-丙酰胺作为 SARD 和泛拮抗剂治疗恩杂鲁胺耐药的前列腺癌

  摘要：

  我们在此报告了作为选择性雄激素受体降解剂 (SARDs) 和泛拮抗剂的新型芳基吡唑-1-基-丙酰胺库的设计、合成和药理学表征，它们具有广泛的 AR 拮抗作用。药理学评估表明，在常见的 A 环-连接-B 环非甾体类抗雄激素的一般药效团中引入吡唑部分作为 B 环结构元件，允许开发具有独特 SARD 和泛拮抗剂活性的新小分子支架甚至与我们最近发布的 AF-1 结合 SARD 相比，例如 UT-155 ( 9 ) 和 UT-34 ( 10）。新型 B 环吡唑表现出有效的 AR 拮抗剂活性，包括有希望的分布、代谢和药代动力学特性，以及广谱 AR 拮抗剂特性，包括有效的体内抗肿瘤活性。26a能够对源自恩杂鲁胺抗性 (Enz-R) VCaP 细胞系的异种移植物诱导 80% 的肿瘤生长抑制。这些结果代表了开发用于治疗 Enz-R 前列腺癌的新型 AR 拮抗剂的进展。

  DOI：

  10.1021/acs.jmedchem.0c00943

文献信息

• Arylisothiocyanato selective androgen receptor modulators (SARMs) for prostate cancer
  作者：Dong Jin Hwang、Jun Yang、Huiping Xu、Igor M. Rakov、Michael L. Mohler、James T. Dalton、Duane D. Miller

  DOI：10.1016/j.bmc.2006.06.019

  日期：2006.10

  the linker sulfone of R-bicalutamide was maintained or replaced with several alternative linkages including ether, amine, N-methylamine, thioether, and methylene (in this case the product was a racemic mixture) functional groups at the X-position. To expand the structure-activity relationship (SAR) of these arylisothiocyanato AR ligands, B-ring halogenated arylisothiocyanato ligands were also prepared

  制备了一系列新的雄激素受体靶向剂（ARTA），并在雄激素依赖性和非依赖性前列腺癌细胞系中进行了测试。这些试剂是具有异硫氰酸根基取代的B环的比卡鲁胺类似物。同样，R-比卡鲁胺的连接基砜被保持或替换为几个可选的连接基，包括醚，胺，N-甲胺，硫醚和亚甲基（在这种情况下，该产品是外消旋混合物）在X位置的官能团。为了扩大这些芳基异硫氰酸根基AR配体的结构活性关系（SAR），还制备并测试了B环卤代芳基异硫氰酸根基配体。芳基异硫氰酸根基AR配体对AR的结合亲和力范围为0.6到54 nM。其中，硫醚和醚键表现出高结合亲和力（0.6和4.6 nM，与雄激素非依赖性前列腺癌细胞系（DU145，PC-3和PPC-1）相比，对LNCaP（一种雄激素依赖性前列腺癌细胞系）分别具有选择性和选择性的细胞生长抑制作用（约3至6倍），并且膀胱细胞系（TSU-Pr1）。但是，配体在正常猴肾细胞系（CV-1）中是无活性的（IC50>
• [EN] SELECTIVE ANDROGEN RECEPTOR DEGRADER (SARD) LIGANDS AND METHODS OF USE THEREOF<br/>[FR] LIGANDS DE SARD - COMPOSÉS DE DÉGRADATION SÉLECTIFS DES RÉCEPTEURS AUX ANDROGÈNES - ET MÉTHODES D'UTILISATION
  申请人：GTX INC

  公开号：WO2016172358A1

  公开（公告）日：2016-10-27

  This invention provides novel indole, indazole, benzimidazole, indoline, quinolone, isoquinoline, and carbazole selective androgen receptor degrader (SARD) compounds, pharmaceutical compositions and uses thereof in treating prostate cancer, advanced prostate cancer, castration resistant prostate cancer, androgenic alopecia or other hyper androgenic dermal diseases, Kennedy's disease, amyotrophic lateral sclerosis (ALS), and uterine fibroids, and to methods for reducing the levels of androgen receptor-full length (AR-FL) including pathogenic and/or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR in a subject.

  这项发明提供了新型吲哚、吲哚唑、苯并咪唑、吲哚啉、喹啉、异喹啉和咔唑选择性雄激素受体降解剂（SARD）化合物，以及在治疗前列腺癌、晚期前列腺癌、去势抵抗性前列腺癌、雄激素性脱发或其他高雄激素皮肤疾病、肯尼迪病、肌萎缩侧索硬化（ALS）和子宫肌瘤方面的药物组合物和用途，以及用于降低受试者体内雄激素受体全长（AR-FL）包括病原性和/或耐药突变、AR剪接变体（AR-SV）和AR病原性多谷氨酸（polyQ）多态性的水平的方法。
• Effect of B-ring substitution pattern on binding mode of propionamide selective androgen receptor modulators
  作者：Casey E. Bohl、Zengru Wu、Jiyun Chen、Michael L. Mohler、Jun Yang、Dong Jin Hwang、Suni Mustafa、Duane D. Miller、Charles E. Bell、James T. Dalton

  DOI：10.1016/j.bmcl.2008.09.002

  日期：2008.10

  Selective androgen receptor modulators (SARMs) are essentially prostate sparing androgens, which provide therapeutic potential in osteoporosis, male hormone replacement, and muscle wasting. Herein we report crystal structures of the androgen receptor (AR) ligand-binding domain (LBD) complexed to a series of potent synthetic nonsteroidal SARMs with a substituted pendant arene referred to as the B-ring

  选择性雄激素受体调节剂 (SARM) 本质上是保护前列腺的雄激素，可为骨质疏松症、男性激素替代和肌肉萎缩提供治疗潜力。在此，我们报告了雄激素受体（AR）配体结合结构域（LBD）与一系列有效的合成非甾体SARMs复合的晶体结构，这些合成非甾体SARMs具有被称为B环的取代的悬挂芳烃。我们发现亲水性 B 环对位取代类似物表现出甾体化合物所未见的额外氢键区域，并且多个卤素取代会影响 B 环构象以及与 Trp741 的芳香相互作用。该信息阐明了对于高 AR 结合亲和力很重要的相互作用，并为基于结构的药物设计提供了新的见解。
• [EN] N-BRIDGED SELECTIVE ANDROGEN RECEPTOR MODULATORS AND METHODS OF USE THEREOF<br/>[FR] MODULATEURS SELECTIFS DU RECEPTEUR DES ANDROGENES N-PONTES ET PROCEDES D'UTILISATION
  申请人：UNIV TENNESSEE RES FOUNDATION

  公开号：WO2003106401A1

  公开（公告）日：2003-12-24

  This invention provides a class of androgen receptor targeting agents (ARTA) The agents define a new subclass of compounds, which are selective androgen receptor modulators (SARM). Several of the SARM compounds have been found to have an unexpected androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. Other SARM compounds have been found to have an unexpected antiandrogenic activity of a nonsteroidal ligand for the androgen receptor. The SARM compounds, either alone or as a composition, are useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and/or prevention of acute and/or chronic muscular wasting conditions; e) preventing and/or treating dry eye conditions; f) oral androgen replacement therapy, and/or g) decreasing the incidence of, halting or causing a regression of prostate cancer.

  这项发明提供了一类雄激素受体靶向药物（ARTA）。这些药物定义了一类新的化合物亚类，即选择性雄激素受体调节剂（SARM）。已发现几种SARM化合物具有非类固醇配体的意外雄激素和合成活性。其他SARM化合物已被发现具有非类固醇配体的意外抗雄激素活性。这些SARM化合物，无论是单独使用还是作为组合物，对以下方面有用：a）男性避孕；b）治疗各种激素相关疾病，例如与老年男性雄激素下降（ADAM）相关的疾病，如疲劳、抑郁、性欲减退、性功能障碍、勃起功能障碍、性腺功能减退、骨质疏松、脱发、贫血、肥胖、骨肌减少症、骨质疏松、良性前列腺增生、情绪和认知变化以及前列腺癌；c）治疗与女性雄激素下降（ADIF）相关的疾病，如性功能障碍、性欲减退、性腺功能减退、骨肌减少症、骨质疏松、认知和情绪变化、抑郁、贫血、脱发、肥胖、子宫内膜异位症、乳腺癌、子宫癌和卵巢癌；d）治疗和/或预防急性和/或慢性肌肉消耗症；e）预防和/或治疗干眼症；f）口服雄激素替代疗法，和/或g）降低前列腺癌的发病率，停止或导致前列腺癌的退化。
• Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics
  作者：Ashley R. Schneekloth、Mathieu Pucheault、Hyun Seop Tae、Craig M. Crews

  DOI：10.1016/j.bmcl.2008.07.114

  日期：2008.11

  We have developed a heterobifunctional all-small molecule PROTAC (PROteolysis TArgeting Chimera) capable of inducing proteasomal degradation of the androgen receptor. This cell permeable PROTAC consists of a non-steroidal androgen receptor ligand (SARM) and the MDM2 ligand known as nutlin, connected by a PEG-based linker. The SARM -nutlin PROTAC recruits the androgen receptor to MDM2, which functions as an E3 ubiquitin ligase. This leads to the ubiquitination of the androgen receptor, and its subsequent degradation by the proteasome. Upon treatment of HeLa cells with 10 mu M PROTAC for 7 h, we were able to observe a decrease in androgen receptor levels. This degradation is proteasome dependent, as it is mitigated in cells pre-treated with 10 mu M epoxomicin, a specific proteasome inhibitor. These results have implications for the potential study and treatment of various cancers with increased androgen receptor levels. (C) 2008 Elsevier Ltd. All rights reserved.