1-(4-((4-amino-3-(6-ethoxynaphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidin-1-yl)ethanone | 1363386-70-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 1-(4-((4-amino-3-(6-ethoxynaphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidin-1-yl)ethanone
• 英文别名: 1-[4-[[4-Amino-3-(6-ethoxy-2-naphthyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-1-piperidyl]ethanone；1-[4-[[4-amino-3-(6-ethoxynaphthalen-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]piperidin-1-yl]ethanone
• CAS: 1363386-70-2
• 化学式: C₂₅H₂₈N₆O₂
• 分子量: 444.536
• InChiKey: BUNKNNOQAMJXHS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  99.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  1-BOC-4-甲磺酰基氧甲基哌啶 在 四(三苯基膦)钯 、 sodium carbonate 、 caesium carbonate 、 三乙胺 、 三氟乙酸 作用下， 以 乙二醇二甲醚 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 1-(4-((4-amino-3-(6-ethoxynaphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidin-1-yl)ethanone
  参考文献：
  名称：

  Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis

  摘要：

  New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activity in vitro and in vivo. Unfortunately, 1 has potent human ether-a-go-go-related gene (hERG) inhibitory activity, associated with long Q-T syndrome, and consequently presents a cardiotoxicity risk. Here, we describe the identification of an optimized TgCDPK1 inhibitor 32, which does not have a hERG liability and possesses a favorable pharmacokinetic profile in small and large animals. 32 is CNS-penetrant and highly effective in acute and latent mouse models of T. gondii infection, significantly reducing the amount of parasite in the brain, spleen, and peritoneal fluid and reducing brain cysts by >85%. These properties make 32 a promising lead for the development of a new antitoxoplasmosis therapy.

  DOI：

  10.1021/acs.jmedchem.6b00760

文献信息

• Development of <i>Toxoplasma gondii</i> Calcium-Dependent Protein Kinase 1 (<i>Tg</i>CDPK1) Inhibitors with Potent Anti-<i>Toxoplasma</i> Activity
  作者：Steven M. Johnson、Ryan C. Murphy、Jennifer A. Geiger、Amy E. DeRocher、Zhongsheng Zhang、Kayode K. Ojo、Eric T. Larson、B. Gayani K. Perera、Edward J. Dale、Panqing He、Molly C. Reid、Anna M. W. Fox、Natascha R. Mueller、Ethan A. Merritt、Erkang Fan、Marilyn Parsons、Wesley C. Van Voorhis、Dustin J. Maly

  DOI：10.1021/jm201713h

  日期：2012.3.8

  Toxoplasmosis is a disease of prominent health concern that is caused by the protozoan parasite Toxoplasma gondii. Proliferation of T. gondii is dependent on its ability to invade host cells, which is mediated in part by calcium-dependent protein kinase 1 (CDPK1). We have developed ATP competitive inhibitors of TgCDPK1 that block invasion of parasites into host cells, preventing their proliferation. The presence of a unique glycine gatekeeper residue in TgCDPK1 permits selective inhibition of the parasite enzyme over human kinases. These potent TgCDPK1 inhibitors do not inhibit the growth of human cell lines and represent promising candidates as toxoplasmosis therapeutics.
• Development of an Orally Available and Central Nervous System (CNS) Penetrant <i>Toxoplasma gondii</i> Calcium-Dependent Protein Kinase 1 (<i>Tg</i>CDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of <i>Toxoplasmosis</i>
  作者：Rama Subba Rao Vidadala、Kasey L. Rivas、Kayode K. Ojo、Matthew A. Hulverson、Jennifer A. Zambriski、Igor Bruzual、Tracey L. Schultz、Wenlin Huang、Zhongsheng Zhang、Suzanne Scheele、Amy E. DeRocher、Ryan Choi、Lynn K. Barrett、Latha Kallur Siddaramaiah、Wim G. J. Hol、Erkang Fan、Ethan A. Merritt、Marilyn Parsons、Gail Freiberg、Kennan Marsh、Dale J. Kempf、Vern B. Carruthers、Nina Isoherranen、J. Stone Doggett、Wesley C. Van Voorhis、Dustin J. Maly

  DOI：10.1021/acs.jmedchem.6b00760

  日期：2016.7.14

  New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activity in vitro and in vivo. Unfortunately, 1 has potent human ether-a-go-go-related gene (hERG) inhibitory activity, associated with long Q-T syndrome, and consequently presents a cardiotoxicity risk. Here, we describe the identification of an optimized TgCDPK1 inhibitor 32, which does not have a hERG liability and possesses a favorable pharmacokinetic profile in small and large animals. 32 is CNS-penetrant and highly effective in acute and latent mouse models of T. gondii infection, significantly reducing the amount of parasite in the brain, spleen, and peritoneal fluid and reducing brain cysts by >85%. These properties make 32 a promising lead for the development of a new antitoxoplasmosis therapy.