(S)-4'-((5-(1-(4-bromophenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)bi phenyl-2-carboxylic acid | 1338259-06-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (S)-4'-((5-(1-(4-bromophenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)bi phenyl-2-carboxylic acid
• 英文别名: (S)-4'-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid；2-[4-[[5-[[(1S)-1-(4-bromophenyl)ethyl]carbamoyl]-2,3-dimethylindol-1-yl]methyl]phenyl]benzoic acid
• CAS: 1338259-06-5
• 化学式: C₃₃H₂₉BrN₂O₃
• 分子量: 581.509
• InChiKey: HBMXDCXJXYASGW-NRFANRHFSA-N

物化性质

• 沸点：
  809.7±65.0 °C(Predicted)
• 密度：
  1.32±0.1 g/cm3(Predicted)
• 溶解度：
  乙醇中≤30mg/ml；DMSO中≤30mg/ml；二甲基甲酰胺中≤30mg/ml

计算性质

• 辛醇/水分配系数(LogP)：
  7.4
• 重原子数：
  39
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  71.3
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (S)-4'-((5-(1-(4-bromophenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)bi phenyl-2-carboxylic acid 、 环丙基硼酸 在 potassium phosphate 、 palladium diacetate 、 三环己基膦 作用下， 以 水 、 甲苯 为溶剂， 反应 1.0h， 生成 (S)-4'-((5-((1-(4-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid
  参考文献：
  名称：

  [EN] PPARG MODULATORS FOR TREATMENT OF OSTEOPOROSIS
  [FR] MODULATEURS DE PPARG POUR LE TRAITEMENT DE L'OSTÉOPOROSE

  摘要：

  本发明提供了一种治疗进行性骨病的方法，如骨质疏松症、佩吉特病、多发性骨髓瘤或甲状旁腺功能亢进症，包括向患有该病的患者施用有效量的非激动剂PPARG调节剂。

  公开号：

  WO2015161108A1
• 作为产物：
  描述：

  1-((2'-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid 在 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.58h， 生成 (S)-4'-((5-(1-(4-bromophenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)bi phenyl-2-carboxylic acid
  参考文献：
  名称：

  N-BIPHENYLMETHYLINDOLE MODULATORS OF PPARG

  摘要：

  该发明提供了与PPARG（PPARγ）结合亲和力高的分子实体，抑制激酶介导的，例如cdk5介导的PPARG磷酸化，但不对PPARG产生激动作用。该发明的化合物可用于治疗患有PPARG起作用的疾病的患者，如糖尿病、胰岛素抵抗、糖耐量受损、糖尿病前期、高血糖、高胰岛素血症、肥胖或炎症。在使用该发明的化合物治疗这些疾病的方法中，该化合物可以避免在接受该化合物的患者中产生明显体重增加、水肿、骨生长或形成受损、心肌肥大或上述任何组合的副作用。该发明还提供了化合物的制备方法、用于评估该发明的化合物作为非激动性PPARG结合化合物的生物测定方法，以及制药组合物。

  公开号：

  US20120309757A1

文献信息

• Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation
  作者：Jang Hyun Choi、Alexander S. Banks、Theodore M. Kamenecka、Scott A. Busby、Michael J. Chalmers、Naresh Kumar、Dana S. Kuruvilla、Youseung Shin、Yuanjun He、John B. Bruning、David P. Marciano、Michael D. Cameron、Dina Laznik、Michael J. Jurczak、Stephan C. Schürer、Dušica Vidović、Gerald I. Shulman、Bruce M. Spiegelman、Patrick R. Griffin

  DOI：10.1038/nature10383

  日期：2011.9

  The nuclear receptor PPARγ is the target of thiazolidinedione antidiabetics including rosiglitazone and pioglitazone. These full PPARγ agonists are effective and well tolerated in most patients, but cause fluid retention and weight gain in a minority. In this proof-of-concept study, Choi et al. show the development of specific PPARγ ligands that retain antidiabetic activity through blockade of Cdk5-mediated PPARγ phosphorylation, but that are not full PPARγ agonists. In mouse models, these ligands do not cause the side effects sometimes associated with full PPARγ agonists. PPARγ is the functioning receptor for the thiazolidinedione (TZD) class of antidiabetes drugs including rosiglitazone and pioglitazone1. These drugs are full classical agonists for this nuclear receptor, but recent data have shown that many PPARγ-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARγ by Cdk5 (ref. 2). Here we describe novel synthetic compounds that have a unique mode of binding to PPARγ, completely lack classical transcriptional agonism and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Moreover, one such compound, SR1664, has potent antidiabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PPARγ drugs. Unlike TZDs, SR1664 also does not interfere with bone formation in culture. These data illustrate that new classes of antidiabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPARγ.

  核受体 PPARγ 是包括罗格列酮和吡格列酮在内的噻唑烷二酮类抗糖尿病药物的靶点。这些全 PPARγ 激动剂对大多数患者有效且耐受性良好，但对少数患者会导致体液潴留和体重增加。在这项概念验证研究中，Choi 等人展示了通过阻断 Cdk5 介导的 PPARγ 磷酸化而保持抗糖尿病活性的特定 PPARγ 配体的开发情况，但这些配体并非完全的 PPARγ 激动剂。在小鼠模型中，这些配体不会产生完全 PPARγ 激动剂有时会产生的副作用。PPARγ 是噻唑烷二酮（TZD）类抗糖尿病药物（包括罗格列酮和吡格列酮1）的功能受体。这些药物是该核受体的完全经典激动剂，但最近的数据显示，许多基于 PPARγ 的药物具有单独的生化活性，即通过 Cdk5 阻止与肥胖相关的 PPARγ 磷酸化（参考文献 2）。在这里，我们描述了一些新型合成化合物，它们与 PPARγ 的结合方式独特，完全没有经典的转录激动作用，而且能在培养的脂肪细胞和胰岛素抵抗小鼠体内阻断 Cdk5 介导的磷酸化。此外，其中一种化合物 SR1664 具有很强的抗糖尿病活性，同时不会导致体液潴留和体重增加，而这正是许多 PPARγ 药物的严重副作用。与 TZDs 不同，SR1664 也不会干扰培养物中骨的形成。这些数据说明，通过特异性靶向 Cdk5 介导的 PPARγ 磷酸化，可以开发出新的抗糖尿病药物。
• N-biphenylmethylindole modulators of PPARG
  申请人：Kamenecka Theodore Mark

  公开号：US08957093B2

  公开（公告）日：2015-02-17

  The invention provides molecular entities that bind with high affinity to PPARG (PPARγ), inhibit kinase-mediated, e.g., cdk5-mediated, phosphorylation of PPARG, but do not exert an agonistic effect on PPARG. Compounds of the invention can be used for treatment of conditions in patients wherein PPARG plays a role, such as diabetes, insulin resistance, impaired glucose tolerance, pre-diabetes, hyperglycemia, hyperinsulinemia, obesity, or inflammation. In methods of treatment of these conditions using a compound of the invention, the compound can avoid producing side effects of significant weight gain, edema, impairment of bone growth or formation, or cardiac hypertrophy, or any combination thereof, in the patient receiving the compound. Methods of preparation of the compounds, bioassay methods for evaluating compounds of the invention as non-agonistic PPARG binding compounds, and pharmaceutical compositions are also provided.

  本发明提供了与PPARG（PPARγ）高亲和力结合、抑制激酶介导的（例如cdk5介导的）PPARG磷酸化但不对PPARG产生激动作用的分子实体。本发明的化合物可用于治疗患有PPARG参与的疾病的患者，如糖尿病、胰岛素抵抗、糖耐量受损、糖尿病前期、高血糖、高胰岛素血症、肥胖或炎症。在使用本发明的化合物进行这些疾病的治疗方法中，该化合物可以避免在接受该化合物的患者中产生显著的体重增加、水肿、骨生长或形成的损伤、心脏肥大或任何组合的副作用。本发明还提供了化合物的制备方法、评估本发明的化合物作为非激动性PPARG结合化合物的生物测定方法以及制药组合物。
• PPARG modulators for treatment of osteoporosis
  申请人：The Scripps Research Institute

  公开号：US10016394B2

  公开（公告）日：2018-07-10

  The invention provides methods of treatment of a progressive bone disease, such as osteoporosis, Paget's Disease, multiple myeloma, or hyperparathyroidism, comprising administration of an effective amount of a non-agonist PPARG modulator to a patient afflicted with the disease.

  本发明提供了治疗进行性骨病（如骨质疏松症、帕吉特氏病、多发性骨髓瘤或甲状旁腺功能亢进症）的方法，包括向患病患者施用有效量的非拮抗剂 PPARG 调节剂。
• PPARG modulators for the treatment of osteoporosis
  申请人：The Scripps Research Institute

  公开号：US10744117B2

  公开（公告）日：2020-08-18

  The invention provides methods of treatment of a progressive bone disease, such as osteoporosis, Paget's Disease, multiple myeloma, or hyperparathyroidism, comprising administration of an effective amount of a non-agonist PPARG modulator to a patient afflicted with the disease.

  本发明提供了治疗进行性骨病（如骨质疏松症、帕吉特氏病、多发性骨髓瘤或甲状旁腺功能亢进症）的方法，包括向患病患者施用有效量的非拮抗剂 PPARG 调节剂。
• Design, Synthesis, and Biological Evaluation of Indole Biphenylcarboxylic Acids as PPARγ Antagonists
  作者：Alice Asteian、Anne-Laure Blayo、Yuanjun He、Marcel Koenig、Youseung Shin、Dana S. Kuruvilla、Cesar A. Corzo、Michael D. Cameron、Li Lin、Claudia Ruiz、Susan Khan、Naresh Kumar、Scott Busby、David P. Marciano、Ruben D. Garcia-Ordonez、Patrick R. Griffin、Theodore M. Kamenecka

  DOI：10.1021/acsmedchemlett.5b00218

  日期：2015.9.10

  The thiazolidinediones (TZD) typified by rosiglitazone are the only approved therapeutics targeting PPAR gamma for the treatment of type-2 diabetes (T2DM). Unfortunately, despite robust insulin sensitizing properties, they are accompanied by a number of severe side effects including congestive heart failure, edema, weight gain, and osteoporosis. We recently identified PPAR gamma antagonists that bind reversibly with high affinity but do not induce transactivation of the receptor, yet they act as insulin sensitizers in mouse models of diabetes (SR1664).(1) This Letter details our synthetic exploration around this novel series of PPAR gamma antagonists based on an N-biphenylmethylindole scaffold. Structure-activity relationship studies led to the identification of compound 46 as a high affinity PPAR gamma antagonist that exhibits antidiabetic properties following oral administration in diet-induced obese mice.