1-(5-(1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-N-(2-methylcyclohexyl)piperidine-4-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 1-(5-(1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-N-(2-methylcyclohexyl)piperidine-4-carboxamide
• 英文别名: N-(2-methylcyclohexyl)-1-(5-pyrazol-1-yl-1,3,4-thiadiazol-2-yl)piperidine-4-carboxamide
• 化学式: C₁₈H₂₆N₆OS
• 分子量: 374.51
• InChiKey: FDVRGUKZYCSFRL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  104
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  ethyl 1-(5-bromo-1,3,4-thiadiazol-2-yl)piperidine-4-carboxylate 在 盐酸 、 hydrazine hydrate 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 lithium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 31.0h， 生成 1-(5-(1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-N-(2-methylcyclohexyl)piperidine-4-carboxamide
  参考文献：
  名称：

  Structural optimization on a virtual screening hit of smoothened receptor

  摘要：

  The Hedgehog (Hh) pathway plays a critical role during embryonic development by controlling cell patterning, growth and migration. In adults, the function of Hh pathway is curtailed to tissue repair and maintenance. Aberrant reactivation of Hh signaling has been linked to tumorigenesis in various cancers, such as basal cell carcinoma (BCC) and medulloblastoma. The Smoothened (Smo) receptor, a key component of the Hh pathway which is central to the signaling transduction, has emerged as an attractive therapeutic target for the treatment of human cancers. Taking advantage of the availability of several crystal structures of Smo in complex with different antagonists, we have previously conducted a molecular docking-based virtual screening to identify several compounds which exhibited significant inhibitory activity against the Hh pathway activation (IC50 < 10 mu M) in a Gli-responsive element (GRE) reporter gene assay. The most potent compound (ChemDiv ID C794-1677: 47 nM) showed comparable Hh signaling inhibition to the marketed drug vismodegib (46 nM). Herein, we report our structural optimization based on the virtual screening hit C794-1677. Our efforts are aimed to improve potency, decrease cLogP, and remove potentially metabolic labile/toxic pyrrole and aniline functionalities presented in C794-1677. The optimization led to the identification of numerous potent compounds exemplified by 25 (7.1 nM), which was 7 folds more potent compared with vismodegib. In addition, 25 was much less lipophilic compared with C794-1677 and devoid of the potentially metabolic labile/toxic pyrrole and aniline functional groups. Furthermore, 25 exhibited promising efficacy in inhibiting Gli1 mRNA expression in NIH3T3 cells with either wildtype Smo or D473H Smo mutant. These results represented significant improvement over the virtual screening hit C794-1677 and suggested that compound 25 can be used as a good starting point to support lead optimization. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.03.057

文献信息

• Structural optimization on a virtual screening hit of smoothened receptor
  作者：Shiwei Song、Jinyi Jiang、Li Zhao、Qin Wang、Wenfeng Lu、Chaonan Zheng、Jie Zhang、Haikuo Ma、Sheng Tian、Jiyue Zheng、Lusong Luo、Youyong Li、Zeng-Jie Yang、Xiaohu Zhang

  DOI：10.1016/j.ejmech.2019.03.057

  日期：2019.6

  The Hedgehog (Hh) pathway plays a critical role during embryonic development by controlling cell patterning, growth and migration. In adults, the function of Hh pathway is curtailed to tissue repair and maintenance. Aberrant reactivation of Hh signaling has been linked to tumorigenesis in various cancers, such as basal cell carcinoma (BCC) and medulloblastoma. The Smoothened (Smo) receptor, a key component of the Hh pathway which is central to the signaling transduction, has emerged as an attractive therapeutic target for the treatment of human cancers. Taking advantage of the availability of several crystal structures of Smo in complex with different antagonists, we have previously conducted a molecular docking-based virtual screening to identify several compounds which exhibited significant inhibitory activity against the Hh pathway activation (IC50 < 10 mu M) in a Gli-responsive element (GRE) reporter gene assay. The most potent compound (ChemDiv ID C794-1677: 47 nM) showed comparable Hh signaling inhibition to the marketed drug vismodegib (46 nM). Herein, we report our structural optimization based on the virtual screening hit C794-1677. Our efforts are aimed to improve potency, decrease cLogP, and remove potentially metabolic labile/toxic pyrrole and aniline functionalities presented in C794-1677. The optimization led to the identification of numerous potent compounds exemplified by 25 (7.1 nM), which was 7 folds more potent compared with vismodegib. In addition, 25 was much less lipophilic compared with C794-1677 and devoid of the potentially metabolic labile/toxic pyrrole and aniline functional groups. Furthermore, 25 exhibited promising efficacy in inhibiting Gli1 mRNA expression in NIH3T3 cells with either wildtype Smo or D473H Smo mutant. These results represented significant improvement over the virtual screening hit C794-1677 and suggested that compound 25 can be used as a good starting point to support lead optimization. (C) 2019 Elsevier Masson SAS. All rights reserved.