4-(2-fluoro-4-(methylsulfonyl)phenoxy)-5-methyl-6-(1-(4-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yloxy)pyrimidine | 1609431-35-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-(2-fluoro-4-(methylsulfonyl)phenoxy)-5-methyl-6-(1-(4-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yloxy)pyrimidine
• 英文别名: 4-(2-Fluoro-4-methylsulfonylphenoxy)-5-methyl-6-[1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl]oxypyrimidine；4-(2-fluoro-4-methylsulfonylphenoxy)-5-methyl-6-[1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl]oxypyrimidine
• CAS: 1609431-35-7
• 化学式: C₂₂H₂₁F₄N₅O₄S
• 分子量: 527.499
• InChiKey: QZVZBCGPKHQJJQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  36
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  116
• 氢给体数：
  0
• 氢受体数：
  13

反应信息

• 作为产物：
  描述：

  2-氯-4-三氟甲基嘧啶 在 potassium tert-butylate 、 potassium carbonate 、 三乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基乙酰胺 、 异丙醇 为溶剂， 反应 9.5h， 生成 4-(2-fluoro-4-(methylsulfonyl)phenoxy)-5-methyl-6-(1-(4-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yloxy)pyrimidine
  参考文献：
  名称：

  [EN] ANTAGONISTS OF GPR119 RECEPTOR AND THE TREATMENT OF DISORDERS RELATED THERETO
  [FR] ANTAGONISTES DU RÉCEPTEUR GPR119 ET TRAITEMENT DE TROUBLES ASSOCIÉS À CEUX-CI

  摘要：

  本发明涉及公式I的化合物及其药物可接受的盐、溶剂化合物和水合物，它们是GPR119的拮抗剂，可用于治疗例如肥胖和与肥胖相关的疾病/病况，如充血性心力衰竭、多囊卵巢综合症、不孕症、胃食管反流病、胆石症（胆结石）、疝气、勃起功能障碍、尿失禁、慢性肾衰竭、淋巴水肿、骨关节炎、高尿酸血症、腰痛、中风、头痛、哮喘和固定性等疾病。此外，本发明的GPR119拮抗剂还可用于治疗非酒精性脂肪性肝病、食物依赖性库欣综合症和癌症（例如食管癌、子宫内膜癌、卵巢癌、肾癌、胰腺癌和乳腺癌；白血病、多发性骨髓瘤、非何杰金淋巴瘤和结肠直肠癌）。

  公开号：

  WO2014074700A1

文献信息

• [EN] ANTAGONISTS OF GPR119 RECEPTOR AND THE TREATMENT OF DISORDERS RELATED THERETO<br/>[FR] ANTAGONISTES DU RÉCEPTEUR GPR119 ET TRAITEMENT DE TROUBLES ASSOCIÉS À CEUX-CI
  申请人：ARENA PHARM INC

  公开号：WO2014074700A1

  公开（公告）日：2014-05-15

  The present invention relates to compounds of Formula I and pharmaceutically acceptable salts, solvates, and hydrates thereof, that are antagonists of GPR119 useful in the treatment of, for example, a disorder selected from: obesity and diseases/conditions related to obesity such as congestive heart failure, polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility. In addition, the present antagonists of GPR119 are useful for treating non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer (e.g., cancers of the esophagus, uterine lining, ovary, kidney, pancreas, and breast; leukemia, multiple myeloma, non-Hodgkin's lymphoma, and colorectal cancer).

  本发明涉及公式I的化合物及其药物可接受的盐、溶剂化合物和水合物，它们是GPR119的拮抗剂，可用于治疗例如肥胖和与肥胖相关的疾病/病况，如充血性心力衰竭、多囊卵巢综合症、不孕症、胃食管反流病、胆石症（胆结石）、疝气、勃起功能障碍、尿失禁、慢性肾衰竭、淋巴水肿、骨关节炎、高尿酸血症、腰痛、中风、头痛、哮喘和固定性等疾病。此外，本发明的GPR119拮抗剂还可用于治疗非酒精性脂肪性肝病、食物依赖性库欣综合症和癌症（例如食管癌、子宫内膜癌、卵巢癌、肾癌、胰腺癌和乳腺癌；白血病、多发性骨髓瘤、非何杰金淋巴瘤和结肠直肠癌）。
• Structural basis for constitutive activity and agonist-induced activation of the enteroendocrine fat sensor GPR119
  作者：M S Engelstoft、C Norn、M Hauge、N D Holliday、L Elster、J Lehmann、R M Jones、T M Frimurer、T W Schwartz

  DOI：10.1111/bph.12877

  日期：2014.12

  Background and PurposeGPR119 is a Gαs‐coupled 7TM receptor activated by endogenous lipids such as oleoylethanolamide (OEA) and by the dietary triglyceride metabolite 2‐monoacylglycerol. GPR119 stimulates enteroendocrine hormone and insulin secretion. But despite massive drug discovery efforts in the field, very little is known about the basic molecular pharmacology of GPR119.Experimental ApproachGPR119 receptor signalling was studied in transfected cells. Mutational mapping (30 mutations in 23 positions) was performed on residues required for ligand‐independent and agonist‐induced GPR119 activation (AR231453 and OEA). Novel Rosetta‐based receptor modelling was applied, using a composite template approach with segments from different X‐ray structures and fully flexible ligand docking.Key ResultsThe increased signalling induced by increasing the cell surface expression of GPR119 in the absence of agonist and the inhibitory effect of two synthetic inverse agonists demonstrated that GRP119 signals with a high degree of constitutive activity through the Gαs pathway. The mutational maps for AR231453 and OEA were very similar and, surprisingly, also similar to the mutational map for residues affecting the constitutive signalling – albeit with key differences. Surprisingly, almost all residues in extracellular loop‐2b were important for the constitutive activity. The molecular modelling and docking demonstrated that AR231453 binds in a ‘vertical’ pocket in between mutational hits reaching from the centre of the receptor out to extracellular loop‐2b.Conclusions and ImplicationsThe high constitutive activity of GPR119 should be taken into account in future drug discovery efforts, which can now be guided by the detailed knowledge of the physiochemical properties of the extended ligand‐binding pocket.