6-(3,4-dihydro-1'H-spiro[chromene-2,4'-piperidin]-1'-yl)-N-(2-pyridin-3-ylethyl)pyridazine-3-carboxamide | 1024604-24-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: 6-(3,4-dihydro-1'H-spiro[chromene-2,4'-piperidin]-1'-yl)-N-(2-pyridin-3-ylethyl)pyridazine-3-carboxamide
• 英文别名: N-(2-pyridin-3-ylethyl)-6-spiro[3,4-dihydrochromene-2,4'-piperidine]-1'-ylpyridazine-3-carboxamide
• CAS: 1024604-24-7
• 化学式: C₂₅H₂₇N₅O₂
• 分子量: 429.522
• InChiKey: AMHNOTDEEQKXPT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  32
• 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：
  80.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  6-chloro-N-(2-(pyridin-3-yl)ethyl)pyridazine-3-carboxamide 、 螺[色满-2,4'-哌啶]盐酸盐 在 三乙胺 作用下， 以 正丁醇 为溶剂， 反应 48.0h， 以98%的产率得到6-(3,4-dihydro-1'H-spiro[chromene-2,4'-piperidin]-1'-yl)-N-(2-pyridin-3-ylethyl)pyridazine-3-carboxamide
  参考文献：
  名称：

  Synthesis and evaluation of novel stearoyl-CoA desaturase 1 inhibitors: 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4′-piperidine] analogs

  摘要：

  In continuation of our investigation on novel stearoyl-CoA desaturase (SCD) 1 inhibitors, we have already reported on the structural modification of the benzoylpiperidines that led to a series of novel and highly potent spiropiperidine-based SCD1 inhibitors. In this report, we would like to extend the scope of our previous investigation and disclose details of the synthesis, SAR, ADME, PK, and pharmacological evaluation of the spiropiperidines with high potency for SCD1 inhibition. Our current efforts have culminated in the identification of 5-fluoro-1'-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4'-piperidine] (10e), which demonstrated a very strong potency for liver SCD1 inhibition (ID(50) = 0.6 mg/kg). This highly efficacious inhibition is presumed to be the result of a combination of strong enzymatic inhibitory activity (IC(50) (mouse)= 2 nM) and good oral bioavailability (F >95%). Pharmacological evaluation of 10e has demonstrated potent, dose-dependent reduction of the plasma desaturation index in C57BL/6J mice on a high carbohydrate diet after a 7-day oral administration (q.d.). In addition, it did not cause any noticeable skin abnormalities up to the highest dose (10 mg/kg). (C) 2010 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2010.07.044

文献信息

• Synthesis and evaluation of novel stearoyl-CoA desaturase 1 inhibitors: 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4′-piperidine] analogs
  作者：Yoshikazu Uto、Yuko Ueno、Yohei Kiyotsuka、Yuriko Miyazawa、Hitoshi Kurata、Tsuneaki Ogata、Makiko Yamada、Tsuneo Deguchi、Masahiro Konishi、Toshiyuki Takagi、Satoko Wakimoto、Jun Ohsumi

  DOI：10.1016/j.ejmech.2010.07.044

  日期：2010.11

  In continuation of our investigation on novel stearoyl-CoA desaturase (SCD) 1 inhibitors, we have already reported on the structural modification of the benzoylpiperidines that led to a series of novel and highly potent spiropiperidine-based SCD1 inhibitors. In this report, we would like to extend the scope of our previous investigation and disclose details of the synthesis, SAR, ADME, PK, and pharmacological evaluation of the spiropiperidines with high potency for SCD1 inhibition. Our current efforts have culminated in the identification of 5-fluoro-1'-6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4'-piperidine] (10e), which demonstrated a very strong potency for liver SCD1 inhibition (ID(50) = 0.6 mg/kg). This highly efficacious inhibition is presumed to be the result of a combination of strong enzymatic inhibitory activity (IC(50) (mouse)= 2 nM) and good oral bioavailability (F >95%). Pharmacological evaluation of 10e has demonstrated potent, dose-dependent reduction of the plasma desaturation index in C57BL/6J mice on a high carbohydrate diet after a 7-day oral administration (q.d.). In addition, it did not cause any noticeable skin abnormalities up to the highest dose (10 mg/kg). (C) 2010 Elsevier Masson SAS. All rights reserved.