(S)-4'-((5-((1-(3-isopropylphenyl)propyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1‘-biphenyl]-2-carboxylic acid | 1415254-54-4

• 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-(3-isopropylphenyl)propyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1‘-biphenyl]-2-carboxylic acid
• 英文别名: (S)-4'-((5-((1-(3-isopropylphenyl)propyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid；2-[4-[[2,3-dimethyl-5-[[(1S)-1-(3-propan-2-ylphenyl)propyl]carbamoyl]indol-1-yl]methyl]phenyl]benzoic acid
• CAS: 1415254-54-4
• 化学式: C₃₇H₃₈N₂O₃
• 分子量: 558.72
• InChiKey: QEJLMMNKULRCIG-UMSFTDKQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.3
• 重原子数：
  42
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  71.3
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  3-异丙基苯甲醛 在 盐酸 、 4-甲基苯磺酸吡啶 、 magnesium sulfate 、 N,N-二异丙基乙胺 、 三氟乙酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 甲醇 、 乙醚 、 二氯甲烷 、 水 为溶剂， 反应 23.08h， 生成 (S)-4'-((5-((1-(3-isopropylphenyl)propyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1‘-biphenyl]-2-carboxylic acid
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Indole Biphenylcarboxylic Acids as PPARγ Antagonists

  摘要：

  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.

  DOI：

  10.1021/acsmedchemlett.5b00218

文献信息

• [EN] PPARG MODULATORS FOR TREATMENT OF OSTEOPOROSIS<br/>[FR] MODULATEURS DE PPARG POUR LE TRAITEMENT DE L'OSTÉOPOROSE
  申请人：SCRIPPS RESEARCH INST

  公开号：WO2015161108A1

  公开（公告）日：2015-10-22

  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。
• N-BIPHENYLMETHYLINDOLE MODULATORS OF PPARG
  申请人：Kamenecka Theodore Mark

  公开号：US20120309757A1

  公开（公告）日：2012-12-06

  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.

  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。
• 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。