2-(5-(2-cyclopropylethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((5-methylthiazol-2-yl)ethynyl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-(5-(2-cyclopropylethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((5-methylthiazol-2-yl)ethynyl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid
• 英文别名: 2-[5-(2-cyclopropylethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]-3-[3-[2-(5-methyl-1,3-thiazol-2-yl)ethynyl]phenyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid
• 化学式: C₃₁H₂₆FN₅O₄S₃
• 分子量: 647.775
• InChiKey: BHYQQSWOTBOXFE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.6
• 重原子数：
  44
• 可旋转键数：
  11
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  206
• 氢给体数：
  2
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  3-环丙基丙酸 在 四氢吡咯 、 三乙烯二胺 、 氯化亚砜 、 magnesium bromide diethyl etherate 、 四丁基氟化铵 、 [P(t-Bu)3]Pd(crotyl)Cl 、 [DTBNpP]Pd(crotyl)Cl 、 caesium carbonate 、 对甲苯磺酸 、 N,N-二异丙基乙胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 二甲基亚砜 为溶剂， 反应 25.67h， 生成 2-(5-(2-cyclopropylethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((5-methylthiazol-2-yl)ethynyl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid
  参考文献：
  名称：

  具有最佳细胞活性和药代动力学特性的基于吡唑的乳酸脱氢酶（LDH）抑制剂。

  摘要：

  乳酸脱氢酶（LDH）催化丙酮酸向乳酸的转化，同时还原的烟酰胺腺嘌呤二核苷酸的氧化是糖酵解途径的最后一步。糖酵解在癌细胞的代谢可塑性中起重要作用，长期以来一直被认为是潜在的治疗靶点。因此，LDH的有效的选择性抑制剂代表了一种有吸引力的治疗方法。然而，迄今为止，药理剂未能实现体内显着的靶标结合，可能是因为蛋白质以非常高的浓度存在于细胞中。我们在此报告了一项领先的优化运动，该研究使用基于结构的设计概念，重点研究了吡唑基系列化合物，并在体外优化了细胞效能药物-靶标的停留时间和体内PK特性，以鉴定可证明LDH在体内具有抑制作用的一流抑制剂。名为NCATS-SM1440（43）和NCATS-SM1441（52）的先导化合物具有进一步研究体内LDH抑制作用所需的属性。

  DOI：

  10.1021/acs.jmedchem.0c00916

文献信息

• 1 H-pyrazol-1-yl-thiazoles as inhibitors of lactate dehydrogenase and methods of use thereof
  申请人：NATIONAL INSTITUTES OF HEALTH, UNITED STATES DEPARTMENT OF HEALTH AND HUMAN SERVICES

  公开号：US10954228B2

  公开（公告）日：2021-03-23

  The disclosure provides a compound of the formula (II) and pharmaceutically acceptable salts thereof. The variables, e.g. n, R, R3, R10, X, Y, and Z are defined herein. These compounds act as lactate dehydrogenase inhibitors and are useful for treating cancer and fibrosis. The compounds may be particularly useful for treating forms of cancer in which a metabolic switch from oxidative phosphorylation to glycolysis has occurred. The disclosure also provides pharmaceutical compositions containing a compound of this formula and method for treating patients having cancer, fibrosis, or other conditions in which a metabolic switch from oxidative phosphorylation to glycolysis has occurred.

  本公开提供了式 (II) 的化合物及其药学上可接受的盐类。变量，如 n、R、R3、R10、X、Y 和 Z 在本文中定义。这些化合物作为乳酸脱氢酶抑制剂，可用于治疗癌症和纤维化。这些化合物尤其适用于治疗发生了从氧化磷酸化到糖酵解的代谢转换的癌症。本公开还提供了含有本式化合物的药物组合物，以及治疗癌症、纤维化或其他发生了从氧化磷酸化到糖酵解的代谢转换的患者的方法。
• 1 H-PYRAZOL-1-YL-THIAZOLES AS INHIBITORS OF LACTATE DEHYDROGENASE AND METHODS OF USE THEREOF
  申请人：THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVIC

  公开号：US20190276448A1

  公开（公告）日：2019-09-12

  The disclosure provides a compound of the formula (II) and pharmaceutically acceptable salts thereof. The variables, e.g. n, R, R 3 , R 10 , X, Y, and Z are defined herein. These compounds act as lactate dehydrogenase inhibitors and are useful for treating cancer and fibrosis. The compounds may be particularly useful for treating forms of cancer in which a metabolic switch from oxidative phosphorylation to glycolysis has occurred. The disclosure also provides pharmaceutical compositions containing a compound of this formula and method for treating patients having cancer, fibrosis, or other conditions in which a metabolic switch from oxidative phosphorylation to glycolysis has occurred.
• TREATING PRIMARY OR IDIOPATHIC HYPEROXALURIA WITH SMALL MOLECULE INHIBITORS OF LACTATE DEHYDROGENASE
  申请人：VANDERBILT UNIVERSITY

  公开号：US20210369683A1

  公开（公告）日：2021-12-02

  The disclosure provides methods of treating a patient having primary hyperoxaluria or idiopathic hyperoxaluria comprising administering a therapeutically effective amound of compound of the formula and pharmaceutically acceptable salts, solvates, and hydrates thereof to the patient. The variables, e.g. ring A, n, R, R 3 , R 10 , X, Y, and Z are defined herein. These compounds act as lactate dehydrogenase inhibitors and are useful inhibiting the conversion of glyoxylate to oxalate. When administered to a patient having a disease or disorder associated with elevated oxalate levels, such as PH type 1, type 2, or type 3 or idiopathic hyperoxaluria the compounds prevent or substantially reduce the amount and buildup of oxalate the patient's kidneys, bladder, urinary tract and other parts of the patient's body.