3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-amine | 1174850-85-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-amine
• 英文别名: 5-methyl-2-(2,2,2-trifluoroethyl)pyrazol-3-amine
• CAS: 1174850-85-1
• 化学式: C₆H₈F₃N₃
• mdl: MFCD10699063
• 分子量: 179.145
• InChiKey: YKSZZXJPTNRVQM-UHFFFAOYSA-N

物化性质

• 沸点：
  224.9±40.0 °C(Predicted)
• 密度：
  1.42±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  12
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  43.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-amine 在 sodium ethanolate 、 三乙胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 生成 N-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)-2-(5-phenyl-2H-tetrazol-2-yl)acetamide
  参考文献：
  名称：

  Discovery, synthesis and characterization of a series of (1-alkyl-3-methyl-1H-pyrazol-5-yl)-2-(5-aryl-2H-tetrazol-2-yl)acetamides as novel GIRK1/2 potassium channel activators

  摘要：

  The present study describes the discovery and characterization of a series of 5-aryl-2H-tetrazol-3-ylacetamides as G protein-gated inwardly-rectifying potassium (GIRK) channels activators. Working from an initial hit discovered during a high-throughput screening campaign, we identified a tetrazole scaffold that shifts away from the previously reported urea-based scaffolds while remaining effective GIRK1/2 channel activators. In addition, we evaluated the compounds in Tier 1 DMPK assays and have identified a (3-methyl-1H-pyrazol-1-yl)tetrahydrothiophene-1,1-dioxide head group that imparts interesting and unexpected microsomal stability compared to previously-reported pyrazole head groups.

  DOI：

  10.1016/j.bmcl.2019.01.027
• 作为产物：
  描述：

  3-氨基巴豆腈 、 (2,2,2-trifluoroethyl)hydrazine hydrochloride 在 溶剂黄146 作用下， 以 乙醇 为溶剂， 反应 18.0h， 生成 3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-amine
  参考文献：
  名称：

  Discovery and Characterization of 1H-Pyrazol-5-yl-2-phenylacetamides as Novel, Non-Urea-Containing GIRK1/2 Potassium Channel Activators

  摘要：

  The G protein-gated inwardly-rectifying potassium channels (GIRK, KO) are a family of inward-rectifying potassium channels, and there is significant evidence supporting the roles of GIRKs in a number of physiological processes and as potential targets for numerous indications. Previously reported urea containing molecules as GIRK1/2 preferring activators have had significant pharmacokinetic (PK) liabilities. Here we report a novel series of 1H-pyrazolo-5yl-2-phenylacetamides in an effort to improve upon the PK properties. This series of compounds display nanomolar potency as GIRK1/2 activators with improved brain distribution (rodent K-p > 0.6).

  DOI：

  10.1021/acschemneuro.7b00217

文献信息

• Compound, composition, and method of activating GIRK potassium channel and use of same for treating conditions of interest
  申请人：Vanderbilt University

  公开号：US09067894B1

  公开（公告）日：2015-06-30

  The present invention provides small molecule activators of GIRK potassium channels and methods for use thereof.

  本发明提供了GIRK钾通道的小分子激活剂以及其使用方法。
• Discovery of ‘molecular switches’ within a GIRK activator scaffold that afford selective GIRK inhibitors
  作者：Wandong Wen、Wenjun Wu、Ian M. Romaine、Kristian Kaufmann、Yu Du、Gary A. Sulikowski、C. David Weaver、Craig W. Lindsley

  DOI：10.1016/j.bmcl.2013.06.023

  日期：2013.8

  This letter describes a multi-dimensional SAR campaign based on a potent, efficacious and selective GIRK1/2 activator (similar to 10-fold versus GIRK1/4 and inactive on nonGIRK 1-containing GIRKs, GIRK 2 or GIRK2/3). Further chemical optimization through an iterative parallel synthesis effort identified multiple 'molecular switches' that modulated the mode of pharmacology from activator to inhibitor, as well as engendering varying selectivity profiles for GIRK1/2 and GIRK1/4. Importantly, these compounds were all inactive on nonGIRK1 containing GIRK channels. However, SAR was challenging as subtle structural modifications had large effects on both mode of pharmacology and GIRK1/2 and GIRK1/4 channel selectivity. (C) 2013 Elsevier Ltd. All rights reserved.
• Improvement of Oral Bioavailability of Pyrazolo-Pyridone Inhibitors of the Interaction of DCN1/2 and UBE2M
  作者：Ho Shin Kim、Jared T. Hammill、Daniel C. Scott、Yizhe Chen、Amy L. Rice、William Pistel、Bhuvanesh Singh、Brenda A. Schulman、R. Kiplin Guy

  DOI：10.1021/acs.jmedchem.1c00035

  日期：2021.5.13
• Discovery of Novel Pyrazolo-pyridone DCN1 Inhibitors Controlling Cullin Neddylation
  作者：Ho Shin Kim、Jared T. Hammill、Daniel C. Scott、Yizhe Chen、Jaeki Min、Jonah Rector、Bhuvanesh Singh、Brenda A. Schulman、R. Kiplin Guy

  DOI：10.1021/acs.jmedchem.9b00410

  日期：2019.9.26

  Chemical control of cullin neddylation is attracting increased attention based largely on the successes of the NEDD8-activating enzyme (E1) inhibitor pevonedistat. Recently reported chemical probes enable selective and time-dependent inhibition of downstream members of the neddylation trienzymatic cascade including the co-E3, DCN1. In this work, we report the optimization of a novel class of small molecule inhibitors of the DCN1-UBE2M interaction. Rational X-ray co-structure enabled optimization afforded a 2S-fold improvement in potency relative to the initial screening hit. The potency gains are largely attributed to additional hydrophobic interactions mimicking the N-terminal acetyl group that drives binding of UBE2M to DCN1. The compounds inhibit the protein-protein interaction, block NEDD8 transfer in biochemical assays, engage DCN1 in cells, and selectively reduce the steady-state neddylation of Cul1 and Cul3 in two squamous carcinoma cell lines harboring DCN1 amplification.
• Discovery, synthesis and characterization of a series of (1-alkyl-3-methyl-1H-pyrazol-5-yl)-2-(5-aryl-2H-tetrazol-2-yl)acetamides as novel GIRK1/2 potassium channel activators
  作者：Swagat Sharma、Krystian A. Kozek、Kristopher K. Abney、Sushil Kumar、Nagsen Gautam、Yazen Alnouti、C. David Weaver、Corey R. Hopkins

  DOI：10.1016/j.bmcl.2019.01.027

  日期：2019.3

  The present study describes the discovery and characterization of a series of 5-aryl-2H-tetrazol-3-ylacetamides as G protein-gated inwardly-rectifying potassium (GIRK) channels activators. Working from an initial hit discovered during a high-throughput screening campaign, we identified a tetrazole scaffold that shifts away from the previously reported urea-based scaffolds while remaining effective GIRK1/2 channel activators. In addition, we evaluated the compounds in Tier 1 DMPK assays and have identified a (3-methyl-1H-pyrazol-1-yl)tetrahydrothiophene-1,1-dioxide head group that imparts interesting and unexpected microsomal stability compared to previously-reported pyrazole head groups.