| 2102502-56-5

• 物质功能分类: 化学试剂 - 手性化学试剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• CAS: 2102502-56-5
• 化学式: C₈H₁₃NO₂.ClH
• 分子量: 191.66
• InChiKey: FXYGUPVLDIACMR-IMDDLPMTNA-N

反应信息

• 作为反应物：
  描述：

  2,4-二氯-6-三氟甲基嘧啶 、 在 N,N-二异丙基乙胺 、 sodium hydroxide 、 potassium hydrogensulfate 、 盐酸 作用下， 以 二氯甲烷 、 乙腈 、 甲醇 、 水 为溶剂， 以73 %的产率得到2-[(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid
  参考文献：
  名称：

  SUBSTITUTED 3-AZABICYCLO[3.1.0]HEXANES AS KETOHEXOKINASE INHIBITORS

  摘要：

  本文提供了替代3-氮杂双环[3.1.0]己烷作为酮己糖激酶抑制剂，制备该类化合物的方法，以及包括向需要的哺乳动物施用该类化合物的方法。

  公开号：

  US20170183328A1

文献信息

• [EN] COMBINATIONS COMPRISING BENZODIOXOL AS GLP-1R AGONISTS FOR USE IN THE TREATMENT OF NASH/NAFLD AND RELATED DISEASES<br/>[FR] COMBINAISONS COMPRENANT DU BENZODIOXOL EN TANT QU'AGONISTES DE GLP-1R DESTINÉES À ÊTRE UTILISÉES DANS LE TRAITEMENT DE LA NASH/NAFLD ET DE MALADIES ASSOCIÉES
  申请人：PFIZER

  公开号：WO2020234726A1

  公开（公告）日：2020-11-26

  In part, the invention provides a new combination comprising (1) a GLP-1R agonist and (2) an ACC inhibitor or a DGAT2 inhibitor, or a KHK inhibitor or FXR agonist. The invention further provides new methods for treating diseases and disorders, for example, fatty liver, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepotitis with cirrhosis, and nonalcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma or with a metabolic-related disease, obesity, and type 2 diabetes, for example, using the new combination described herein.

  部分地，该发明提供了一种新的组合，包括（1）GLP-1R激动剂和（2）ACC抑制剂或DGAT2抑制剂，或KHK抑制剂或FXR激动剂。该发明还提供了治疗疾病和疾病的新方法，例如脂肪肝，非酒精性脂肪肝病，非酒精性脂肪性肝炎，伴有肝纤维化的非酒精性脂肪性肝炎，伴有肝硬化的非酒精性脂肪性肝炎，以及伴有肝细胞癌或代谢相关疾病的非酒精性脂肪性肝炎，肥胖和2型糖尿病等，例如，使用本文所述的新组合。
• Discovery of PF-06835919: A Potent Inhibitor of Ketohexokinase (KHK) for the Treatment of Metabolic Disorders Driven by the Overconsumption of Fructose
  作者：Kentaro Futatsugi、Aaron C. Smith、Meihua Tu、Brian Raymer、Kay Ahn、Steven B. Coffey、Matthew S. Dowling、Dilinie P. Fernando、Jemy A. Gutierrez、Kim Huard、Jayasankar Jasti、Amit S. Kalgutkar、John D. Knafels、Jayvardhan Pandit、Kevin D. Parris、Sylvie Perez、Jeffrey A. Pfefferkorn、David A. Price、Tim Ryder、Andre Shavnya、Ingrid A. Stock、Andy S. Tsai、Gregory J. Tesz、Benjamin A. Thuma、Yan Weng、Hanna M. Wisniewska、Gang Xing、Jun Zhou、Thomas V. Magee

  DOI：10.1021/acs.jmedchem.0c00944

  日期：2020.11.25

  Increased fructose consumption and its subsequent metabolism have been implicated in metabolic disorders such as nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH) and insulin resistance. Ketohexokinase (KHK) converts fructose to fructose-1-phosphate (F1P) in the first step of the metabolic cascade. Herein we report the discovery of a first-in-class KHK inhibitor, PF-06835919 (8), currently in phase 2 clinical trials. The discovery of 8 was built upon our originally reported, fragment-derived lead 1 and the recognition of an alternative, rotated binding mode upon changing the ribose-pocket binding moiety from a pyrrolidinyl to an azetidinyl ring system. This new binding mode enabled efficient exploration of the vector directed at the Arg-108 residue, leading to the identification of highly potent 3-azabicyclo[3.1.0]hexane acetic acid-based KHK inhibitors by combined use of parallel medicinal chemistry and structure-based drug design.