5-amino-3-(7-ethoxyquinolin-3-yl)-1-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazole-4-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 5-amino-3-(7-ethoxyquinolin-3-yl)-1-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazole-4-carboxamide
• 英文别名: 5-Amino-3-(7-ethoxyquinolin-3-yl)-1-(3-hydroxy-2,2-dimethylpropyl)pyrazole-4-carboxamide；5-amino-3-(7-ethoxyquinolin-3-yl)-1-(3-hydroxy-2,2-dimethylpropyl)pyrazole-4-carboxamide
• 化学式: C₂₀H₂₅N₅O₃
• 分子量: 383.45
• InChiKey: JNCYMMFOKVMRMU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  129
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2,2-二甲基-3-羟基丙醛 在 盐酸 、 N-溴代丁二酰亚胺(NBS) 、 sodium hydride 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.32h， 生成 5-amino-3-(7-ethoxyquinolin-3-yl)-1-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazole-4-carboxamide
  参考文献：
  名称：

  Development of 5-Aminopyrazole-4-carboxamide-based Bumped-Kinase Inhibitors for Cryptosporidiosis Therapy

  摘要：

  Cryptosporidium is a leading cause of pediatric diarrhea worldwide. Currently, there is neither a vaccine nor a consistently effective drug available for this disease. Selective 5-aminopyrazole-4-carboxamide-based bumped-kinase inhibitors (BKIs) are effective in both in vitro and in vivo models of Cryptosporidium parvum. Potential cardiotoxicity in some BKIs led to the continued exploration of the 5-aminopyrazole-4-carboxamide scaffold to find safe and effective drug candidates for Cryptosporidium. A series of newly designed BKIs were tested for efficacy against C. parvum using in vitro and in vivo (mouse infection model) assays and safety issues. Compound 6 (BKI 1708) was found to be efficacious at 8 mg/kg dosed once daily (QD) for 5 days with no observable signs of toxicity up to 200 mg/kg dosed QD for 7 days. Compound 15 (BKI 1770) was found to be efficacious at 30 mg/kg dosed twice daily (BID) for 5 days with no observable signs of toxicity up to 300 mg/kg dosed QD for 7 days. Compounds 6 and 15 are promising preclinical leads for cryptosporidiosis therapy with acceptable safety parameters and efficacy in the mouse model of cryptosporidiosis.

  DOI：

  10.1021/acs.jmedchem.9b00069

文献信息

• [EN] 5-AMINOPYRAZOLE-4-CARBOXAMIDE INHIBITORS OF CDPK1 FROM T. GONDII AND C. PARVUM<br/>[FR] INHIBITEURS 5-AMINOPYRAZOLE-4-CARBOXAMIDE DE CDPK1 ISSUES DE T. GONDII ET C. PARVUM
  申请人：UNIV WASHINGTON CT COMMERCIALI

  公开号：WO2014189947A1

  公开（公告）日：2014-11-27

  The present disclosure is generally directed to compositions and methods for treating apicomplexan protozoan related disease, such as toxoplasmosis and cryptosporidiosis.

  本公开通常涉及用于治疗顶复门原虫相关疾病的组合物和方法，例如弓形虫病和隐孢子虫病。
• SAR Studies of 5-Aminopyrazole-4-carboxamide Analogues as Potent and Selective Inhibitors of <i>Toxoplasma gondii</i> CDPK1
  作者：Wenlin Huang、Kayode K. Ojo、Zhongsheng Zhang、Kasey Rivas、Rama Subba Rao Vidadala、Suzanne Scheele、Amy E. DeRocher、Ryan Choi、Matthew A. Hulverson、Lynn K. Barrett、Igor Bruzual、Latha Kallur Siddaramaiah、Keshia M. Kerchner、Matthew D. Kurnick、Gail M. Freiberg、Dale Kempf、Wim G. J. Hol、Ethan A. Merritt、Georg Neckermann、Eugenio L. de Hostos、Nina Isoherranen、Dustin J. Maly、Marilyn Parsons、J. Stone Doggett、Wesley C. Van Voorhis、Erkang Fan

  DOI：10.1021/acsmedchemlett.5b00319

  日期：2015.12.10

  We previously discovered compounds based on a 5-aminopyrazole-4-carboxamide scaffold to be potent and selective inhibitors of CDPK1 from T. gondii. The current work, through structure-activity relationship studies, led to the discovery of compounds (34 and 35) with improved characteristics over the starting inhibitor 1 in terms of solubility, plasma exposure after oral administration in mice, or efficacy on parasite growth inhibition. Compounds 34 and 35 were further demonstrated to be more effective than 1 in a mouse infection model and markedly reduced the amount of T. gondii in the brain, spleen, and peritoneal fluid, and 35 given at 20 mg/kg eliminated T. gondii from the peritoneal fluid.
• 5-AMINOPYRAZOLE-4-CARBOXAMIDE INHIBITORS OF CDPK1 FROM T. GONDII AND C. PARVUM
  申请人：University of Washington through its Center for Commercialization

  公开号：EP2999696A1

  公开（公告）日：2016-03-30
• US9518026B2
  申请人：——

  公开号：US9518026B2

  公开（公告）日：2016-12-13
• US9956214B2
  申请人：——

  公开号：US9956214B2

  公开（公告）日：2018-05-01