6-(4-(trifluoromethyl)phenyl)imidazo[2,1-b]thiazole-5-carbaldehyde | 562792-67-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 6-(4-(trifluoromethyl)phenyl)imidazo[2,1-b]thiazole-5-carbaldehyde
• 英文别名: 6-[4-(Trifluoromethyl)phenyl]imidazo[2,1-b]1,3-thiazoline-5-carbaldehyde；6-[4-(trifluoromethyl)phenyl]imidazo[2,1-b][1,3]thiazole-5-carbaldehyde
• CAS: 562792-67-0
• 化学式: C₁₃H₇F₃N₂OS
• 分子量: 296.273
• InChiKey: AYDSJLKRRNTAKO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  62.6
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  6-(4-(trifluoromethyl)phenyl)imidazo[2,1-b]thiazole-5-carbaldehyde 在 sodium tetrahydroborate 、 溶剂黄146 作用下， 以 甲醇 、 乙醇 为溶剂， 生成 2-(3,4-dichlorophenyl)-N-((6-(4-(trifluoromethyl)phenyl)imidazo[2,1-b]thiazol-5-yl)methyl)ethan-1-amine
  参考文献：
  名称：

  Human constitutive androstane receptor agonist DL5016: A novel sensitizer for cyclophosphamide-based chemotherapies

  摘要：

  The DNA alkylating prodrug cyclophosphamide (CPA), alone or in combination with other agents, is one of the most commonly used anti-cancer agents. As a prodrug, CPA is activated by cytochrome P450 2B6 (CYP2B6), which is transcriptionally regulated by the human constitutive androstane receptor (hCAR). Therefore, hCAR agonists represent novel sensitizers for CPA-based therapies. Among known hCAR agonists, compound 6-(4-chlorophenyl)imidazo-[2,1-b]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl) oxime (CITCO) is the most potent and broadly utilized in biological studies. Through structural modification of CITCO, we have developed a novel compound DL5016 (32), which has an EC50 value of 0.66 mu M and E-MAX value of 4.9 when activating hCAR. DL5016 robustly induced the expression of hCAR target gene CYP2B6, at both the mRNA and protein levels, and caused translocation of hCAR from the cytoplasm to the nucleus in human primary hepatocytes. The effects of DL5016 were highlighted by dramatically enhancing the efficacy of CPA-based cytotoxicity to non-Hodgkin lymphoma cells. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.06.031
• 作为产物：
  描述：

  2-溴-4'-(三氟甲基)苯乙酮 在 三氯氧磷 作用下， 以 氯仿 、 丙酮 为溶剂， 反应 5.0h， 生成 6-(4-(trifluoromethyl)phenyl)imidazo[2,1-b]thiazole-5-carbaldehyde
  参考文献：
  名称：

  Cystic Fibrosis: A New Target for 4-Imidazo[2,1-b]thiazole-1,4-dihydropyridines

  摘要：

  The pharmacology of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel has attracted significant interest in recent years with the aim to search for rational new therapies for diseases caused by CFTR malfunction. Mutations that abolish the function of CFTR cause the life-threatening genetic disease cystic fibrosis (CF). The most common cause of CF is the deletion of phenylalanine 508 (Delta F508) in the CFTR chloride channel. Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca2+ channels are also effective potentiators of CFTR gating, able to correct the defective activity of Delta F508 and other CFTR mutants (Mol. Pharmacol. 2005, 68, 1736). For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects (J. Med. Chem. 2008, 51, 1592) to enhance the activity of Delta F508-CFTR. Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity.

  DOI：

  10.1021/jm200199r

文献信息

• Cystic Fibrosis: A New Target for 4-Imidazo[2,1-<i>b</i>]thiazole-1,4-dihydropyridines
  作者：Roberta Budriesi、Pierfranco Ioan、Alberto Leoni、Nicoletta Pedemonte、Alessandra Locatelli、Matteo Micucci、Alberto Chiarini、Luis J. V. Galietta

  DOI：10.1021/jm200199r

  日期：2011.6.9

  The pharmacology of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel has attracted significant interest in recent years with the aim to search for rational new therapies for diseases caused by CFTR malfunction. Mutations that abolish the function of CFTR cause the life-threatening genetic disease cystic fibrosis (CF). The most common cause of CF is the deletion of phenylalanine 508 (Delta F508) in the CFTR chloride channel. Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca2+ channels are also effective potentiators of CFTR gating, able to correct the defective activity of Delta F508 and other CFTR mutants (Mol. Pharmacol. 2005, 68, 1736). For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects (J. Med. Chem. 2008, 51, 1592) to enhance the activity of Delta F508-CFTR. Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity.
• CAR ACTIVATOR AGENTS FOR CYCLOPHOSPHAMIDE-BASED TREATMENTS OF CANCER
  申请人：UNIVERSITY OF MARYLAND, BALTIMORE

  公开号：US20200352915A1

  公开（公告）日：2020-11-12

  The invention relates to selective small molecule human constitutive androstane receptor (hCAR) activators of Formula (I) or (II), pharmaceutical compositions thereof, and use thereof for the treatment of hematologic malignancies and other cancers. The small molecule hCAR activator in combination with CPA based chemotherapy regimen provides a synergistic effect to help promote cytoxicity of the cyclophosphamide (CPA) based anticancer treatments including CHOP regimen (CPA, doxorubicin, vincristine, and prednisone) by preferential induction of CYP2B6 over CYP3A4 and promoting the formation of therapeutically active CPA metabolite 4-OH-CPA.
• Human constitutive androstane receptor agonist DL5016: A novel sensitizer for cyclophosphamide-based chemotherapies
  作者：Dongdong Liang、Linhao Li、Caitlin Lynch、Bryan Mackowiak、William D. Hedrich、Yong Ai、Yue Yin、Scott Heyward、Menghang Xia、Hongbing Wang、Fengtian Xue

  DOI：10.1016/j.ejmech.2019.06.031

  日期：2019.10

  The DNA alkylating prodrug cyclophosphamide (CPA), alone or in combination with other agents, is one of the most commonly used anti-cancer agents. As a prodrug, CPA is activated by cytochrome P450 2B6 (CYP2B6), which is transcriptionally regulated by the human constitutive androstane receptor (hCAR). Therefore, hCAR agonists represent novel sensitizers for CPA-based therapies. Among known hCAR agonists, compound 6-(4-chlorophenyl)imidazo-[2,1-b]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl) oxime (CITCO) is the most potent and broadly utilized in biological studies. Through structural modification of CITCO, we have developed a novel compound DL5016 (32), which has an EC50 value of 0.66 mu M and E-MAX value of 4.9 when activating hCAR. DL5016 robustly induced the expression of hCAR target gene CYP2B6, at both the mRNA and protein levels, and caused translocation of hCAR from the cytoplasm to the nucleus in human primary hepatocytes. The effects of DL5016 were highlighted by dramatically enhancing the efficacy of CPA-based cytotoxicity to non-Hodgkin lymphoma cells. (C) 2019 Elsevier Masson SAS. All rights reserved.
• DL5050, a Selective Agonist for the Human Constitutive Androstane Receptor
  作者：Dongdong Liang、Linhao Li、Caitlin Lynch、Benjamin Diethelm-Varela、Menghang Xia、Fengtian Xue、Hongbing Wang

  DOI：10.1021/acsmedchemlett.9b00079

  日期：2019.7.11

  The constitutive androstane receptor (CAR) is a xenobiotic sensor governing the transcription of genes involved in drug disposition, energy homeostasis, and cell proliferation. However, currently available human CAR (hCAR) agonists are nonselective, which commonly activate hCAR along with other nuclear receptors, especially the closely related human pregnane X receptor (hPXR). Using a well-known hCAR agonist CITCO as a template, we report our efforts in the discovery of a potent and highly selective hCAR agonist. Two of the new compounds of the series, 18 and 19 (DL5050), demonstrated excellent potency and selectivity for hCAR over hPXR. DL5050 preferentially induced the expression of CYP2B6 (target of hCAR) over CYP3A4 (target of hPXR) on both the mRNA and protein levels. The selective hCAR agonist DL5050 represents a valuable tool molecule to further define the biological functions of hCAR, and may also be used as a new lead in the discovery of hCAR agonists for various therapeutic applications.