tert-butyl 4-((4-amino-3-(6-hydroxynaphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1-carboxylate | 1363386-50-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: tert-butyl 4-((4-amino-3-(6-hydroxynaphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1-carboxylate
• 英文别名: Tert-butyl 4-[[4-amino-3-(6-hydroxynaphthalen-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]piperidine-1-carboxylate
• CAS: 1363386-50-8
• 化学式: C₂₆H₃₀N₆O₃
• 分子量: 474.563
• InChiKey: GQWNZYKUEGYBNV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  35
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  119
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-((4-amino-3-(6-hydroxynaphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1-carboxylate 在 potassium carbonate 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 3-(6-isopropoxynaphthalen-2-yl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
  参考文献：
  名称：

  Development of Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitors with Potent Anti-Toxoplasma Activity

  摘要：

  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.

  DOI：

  10.1021/jm201713h
• 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 、 水 、 sodium carbonate 、 caesium carbonate 作用下， 以 乙二醇二甲醚 、 N,N-二甲基甲酰胺 为溶剂， 反应 19.0h， 生成 tert-butyl 4-((4-amino-3-(6-hydroxynaphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1-carboxylate
  参考文献：
  名称：

  Development of Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitors with Potent Anti-Toxoplasma Activity

  摘要：

  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.

  DOI：

  10.1021/jm201713h

文献信息

• [EN] BUMPED KINASE INHIBITOR COMPOSITIONS AND METHODS FOR TREATING CANCER<br/>[FR] COMPOSITIONS D'INHIBITEUR DE KINASE À BOSSES ET MÉTHODES DE TRAITEMENT DU CANCER
  申请人：UNIV WASHINGTON

  公开号：WO2016123151A1

  公开（公告）日：2016-08-04

  The present disclosure is generally directed to bumped kinase inhibitor (BKI) compositions and methods for treating cancer.

  本公开涉及通常用于治疗癌症的凸起激酶抑制剂（BKI）组合物和方法。
• Compositions and methods for treating toxoplasmosis, cryptosporidiosis and other apicomplexan protozoan related diseases
  申请人：UNIVERSITY OF WASHINGTON

  公开号：US10307425B2

  公开（公告）日：2019-06-04

  The present disclosure is directed to compositions and methods for inhibiting either Toxoplasma gondii (T. gondii) calcium dependent protein kinases (TgCDPKs) or Cryptosporidium parvum (C. parvum) and Cryptosporidium hominus (C. hominus) calcium dependent protein kinases (CpCDPKs) using pyrazolopyrimidine and/or imidazo[1,5-α]pyrazine inhibitors, of the Formula (I), wherein the variables X, Y, Z, R1, and R3 are defined herein.

  本公开涉及使用吡唑嘧啶和/或咪唑并[1,5-α]吡嗪抑制剂抑制弓形虫（T. gondii）钙依赖性蛋白激酶（TgCDPKs）或隐孢子虫（C. parvum）和隐孢子虫（C. hominus）钙依赖性蛋白激酶（CpCDPKs）的组合物和方法。或咪唑并[1,5-α]吡嗪抑制剂，其中变量 X、Y、Z、R1 和 R3 在本文中定义。
• Bumped kinase inhibitor compositions and methods for treating cancer
  申请人：UNIVERSITY OF WASHINGTON

  公开号：US10350211B2

  公开（公告）日：2019-07-16

  The present disclosure is generally directed to bumped kinase inhibitor (BKI) compositions and methods for treating cancer.

  本公开总体上针对治疗癌症的撞击激酶抑制剂（BKI）组合物和方法。
• 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.
• Development of potent and selective Plasmodium falciparum calcium-dependent protein kinase 4 (PfCDPK4) inhibitors that block the transmission of malaria to mosquitoes
  作者：Rama Subba Rao Vidadala、Kayode K. Ojo、Steven M. Johnson、Zhongsheng Zhang、Stephen E. Leonard、Arinjay Mitra、Ryan Choi、Molly C. Reid、Katelyn R. Keyloun、Anna M.W. Fox、Mark Kennedy、Tiffany Silver-Brace、Jen C.C. Hume、Stefan Kappe、Christophe L.M.J. Verlinde、Erkang Fan、Ethan A. Merritt、Wesley C. Van Voorhis、Dustin J. Maly

  DOI：10.1016/j.ejmech.2013.12.048

  日期：2014.3

  Malaria remains a major health concern for a large percentage of the world's population. While great strides have been made in reducing mortality due to malaria, new strategies and therapies are still needed. Therapies that are capable of blocking the transmission of Plasmodium parasites are particularly attractive, but only primaquine accomplishes this, and toxicity issues hamper its widespread use. In this study, we describe a series of pyrazolopyrimidine- and imidazopyrazine-based compounds that are potent inhibitors of PfCDPK4, which is a calcium-activated Plasmodium protein lcinase that is essential for exflagellation of male gametocytes. Thus, PfCDPK4 is essential for the sexual development of Plasmodium parasites and their ability to infect mosquitoes. We demonstrate that two structural features in the ATPbinding site of PfCDPK4 can be exploited in order to obtain potent and selective inhibitors of this enzyme. Furthermore, we demonstrate that pyrazolopyrimidine-based inhibitors that are potent inhibitors of the in vitro activity of PfCDPK4 are also able to block Plasmodium falciparum exflagellation with no observable toxicity to human cells. This medicinal chemistry effort serves as a valuable starting point in the development of safe, transmission-blocking agents for the control of malaria. (C) 2014 Elsevier Masson SAS. All rights reserved.